{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T22:19:59Z","timestamp":1790720399494,"version":"4.1.0"},"reference-count":254,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,10,23]],"date-time":"2021-10-23T00:00:00Z","timestamp":1634947200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Gram-positive bacteria are ancient organisms. Many bacteria, including Gram-positive bacteria, produce toxins to manipulate the host, leading to various diseases. While the targets of Gram-positive bacterial toxins are diverse, many of those toxins use a similar mechanism to invade host cells and exert their functions. Clostridial neurotoxins produced by Clostridial tetani and Clostridial botulinum provide a classical example to illustrate the structure\u2013function relationship of bacterial toxins. Here, we critically review the recent progress of the structure\u2013function relationship of clostridial neurotoxins, including the diversity of the clostridial neurotoxins, the mode of actions, and the flexible structures required for the activation of toxins. The mechanism clostridial neurotoxins use for triggering their activity is shared with many other Gram-positive bacterial toxins, especially molten globule-type structures. This review also summarizes the implications of the molten globule-type flexible structures to other Gram-positive bacterial toxins. Understanding these highly dynamic flexible structures in solution and their role in the function of bacterial toxins not only fills in the missing link of the high-resolution structures from X-ray crystallography but also provides vital information for better designing antidotes against those toxins.<\/jats:p>","DOI":"10.3390\/microorganisms9112206","type":"journal-article","created":{"date-parts":[[2021,10,24]],"date-time":"2021-10-24T22:07:11Z","timestamp":1635113231000},"page":"2206","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Clostridial Neurotoxins: Structure, Function and Implications to Other Bacterial Toxins"],"prefix":"10.3390","volume":"9","author":[{"given":"Shuowei","family":"Cai","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Massachusetts Dartmouth, Dartmouth, MA 02747, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raj","family":"Kumar","sequence":"additional","affiliation":[{"name":"Botulinum Research Center, Institute of Advanced Sciences, Dartmouth, MA 02747, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bal Ram","family":"Singh","sequence":"additional","affiliation":[{"name":"Botulinum Research Center, Institute of Advanced Sciences, Dartmouth, MA 02747, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kumar, R., Feltrup, T.M., Kukreja, R.V., Patel, K.B., Cai, S., and Singh, B.R. (2019). Evolutionary Features in the Structure and Function of Bacterial Toxins. Toxins, 11.","DOI":"10.3390\/toxins11010015"},{"key":"ref_2","unstructured":"Baron, S. (1996). Bacterial Pathogenesis. Medical Microbiology, University of Texas Medical Branch at Galveston."},{"key":"ref_3","first-page":"33","article-title":"Bacterial toxins as virulence factors: Shiga bacillus dysentery viewed as a toxinosis","volume":"44","author":"Keusch","year":"1977","journal-title":"Mt. Sinai J. Med. N. Y."},{"key":"ref_4","unstructured":"(2021, October 15). Todar, Kenneth Bacterial Protein Toxins. Available online: http:\/\/textbookofbacteriology.net\/proteintoxins.html."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"213","DOI":"10.4161\/viru.27024","article-title":"Gram-positive and gram-negative bacterial toxins in sepsis","volume":"5","author":"Ramachandran","year":"2014","journal-title":"Virulence"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/S0934-8840(96)80095-8","article-title":"Molecular Mechanisms of Action of Bacterial Exotoxins","volume":"284","author":"Balfanz","year":"1996","journal-title":"Zent. Bakteriol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.2217\/fmb.09.72","article-title":"Clostridial toxins","volume":"4","author":"Popoff","year":"2009","journal-title":"Future Microbiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/BF03033925","article-title":"Botulinum neurotoxin structure, engineering, and novel cellular trafficking and targeting","volume":"9","author":"Singh","year":"2006","journal-title":"Neurotox. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"294","DOI":"10.3390\/toxins3030294","article-title":"Mechanism of Diphtheria Toxin Catalytic Domain Delivery to the Eukaryotic Cell Cytosol and the Cellular Factors that Directly Participate in the Process","volume":"3","author":"Murphy","year":"2011","journal-title":"Toxins"},{"key":"ref_10","unstructured":"(2021, September 24). Dorlands Medical Dictionary: Enterotoxin. Available online: https:\/\/web.archive.org\/web\/20091207052257\/http:\/\/www.mercksource.com\/pp\/us\/cns\/cns_hl_dorlands_split.jsp?pg=\/ppdocs\/us\/common\/dorlands\/dorland\/three\/000035767.htm."},{"key":"ref_11","first-page":"147","article-title":"Bacterial enterotoxins: Structure, mode of action","volume":"22","author":"Lucas","year":"1991","journal-title":"Ann. Rech. Vet. Ann. Vet. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1136\/jnnp.69.3.292","article-title":"Tetanus","volume":"69","author":"Farrar","year":"2000","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1080\/10408410701364562","article-title":"Botulism diagnostics: From clinical symptoms to in vitro assays","volume":"33","author":"Cai","year":"2007","journal-title":"Crit. Rev. Microbiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1086\/444507","article-title":"Botulism","volume":"41","author":"Sobel","year":"2005","journal-title":"Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1001\/jama.285.8.1059","article-title":"Botulinum toxin as a biological weapon: Medical and public health management","volume":"285","author":"Arnon","year":"2001","journal-title":"JAMA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1111\/bcpt.13048","article-title":"Iatrogenic Botulism Outbreak in Egypt due to a Counterfeit Botulinum Toxin A Preparation\u2014A Descriptive Series of Patient Features and Outcome","volume":"123","author":"Rashid","year":"2018","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Harris, R.A., Anniballi, F., and Austin, J.W. (2020). Adult Intestinal Toxemia Botulism. Toxins, 12.","DOI":"10.3390\/toxins12020081"},{"key":"ref_18","first-page":"102","article-title":"Case of iatrogenic botulism after botulinotherapy in clinical practice","volume":"90","author":"Ibatullin","year":"2018","journal-title":"Ter. Arkh."},{"key":"ref_19","unstructured":"Jeffery, I.A., and Karim, S. (2021). Botulism. StatPearls, StatPearls Publishing."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Garrigues, L., Do, T.D., Bideaux, C., Guillouet, S.E., and Meynial-Salles, I. (2021). Insights into Clostridium tetani: From genome to bioreactors. Biotechnol. Adv., 107781.","DOI":"10.1016\/j.biotechadv.2021.107781"},{"key":"ref_21","unstructured":"(2021, July 19). Genome List\u2014Genome\u2014NCBI, Available online: https:\/\/www.ncbi.nlm.nih.gov\/genome\/browse\/#!\/prokaryotes\/1098\/."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Cohen, J.E., Wang, R., Shen, R.-F., Wu, W.W., and Keller, J.E. (2017). Comparative pathogenomics of Clostridium tetani. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0182909"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.resmic.2014.09.007","article-title":"Historical and current perspectives on Clostridium botulinum diversity","volume":"166","author":"Smith","year":"2015","journal-title":"Res. Microbiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1146\/annurev-biochem-013118-111654","article-title":"Botulinum and Tetanus Neurotoxins","volume":"88","author":"Dong","year":"2019","journal-title":"Annu. Rev. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1093\/infdis\/jit449","article-title":"A Novel Strain of Clostridium botulinum That Produces Type B and Type H Botulinum Toxins","volume":"209","author":"Barash","year":"2014","journal-title":"J. Infect. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1093\/infdis\/jit450","article-title":"Molecular characterization of a novel botulinum neurotoxin type H gene","volume":"209","author":"Dover","year":"2014","journal-title":"J. Infect. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1093\/infdis\/jiv327","article-title":"A Novel Botulinum Neurotoxin, Previously Reported as Serotype H, Has a Hybrid-Like Structure With Regions of Similarity to the Structures of Serotypes A and F and Is Neutralized With Serotype A Antitoxin","volume":"213","author":"Maslanka","year":"2016","journal-title":"J. Infect. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e00100-15","DOI":"10.1128\/mSphere.00100-15","article-title":"Purification and Characterization of Botulinum Neurotoxin FA from a Genetically Modified Clostridium botulinum Strain","volume":"1","author":"Pellett","year":"2016","journal-title":"mSphere"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1093\/infdis\/jiv770","article-title":"Immunological Characterization and Neutralizing Ability of Monoclonal Antibodies Directed Against Botulinum Neurotoxin Type H","volume":"213","author":"Fan","year":"2016","journal-title":"J. Infect. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3911","DOI":"10.1021\/ac504716v","article-title":"Functional characterization of botulinum neurotoxin serotype H as a hybrid of known serotypes F and A (BoNT F\/A)","volume":"87","author":"Kalb","year":"2015","journal-title":"Anal. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1038\/s41467-017-01534-z","article-title":"Structural basis for the unique ganglioside and cell membrane recognition mechanism of botulinum neurotoxin DC","volume":"8","author":"Zhang","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4518","DOI":"10.1038\/s41598-018-22842-4","article-title":"Structural characterisation of the catalytic domain of botulinum neurotoxin X\u2014High activity and unique substrate specificity","volume":"8","author":"Masuyer","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Peck, M.W., Smith, T.J., Anniballi, F., Austin, J.W., Bano, L., Bradshaw, M., Cuervo, P., Cheng, L.W., Derman, Y., and Dorner, B.G. (2017). Historical Perspectives and Guidelines for Botulinum Neurotoxin Subtype Nomenclature. Toxins, 9.","DOI":"10.3390\/toxins9010038"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1128\/JB.01180-06","article-title":"Genetic diversity among Botulinum Neurotoxin-producing clostridial strains","volume":"189","author":"Hill","year":"2007","journal-title":"J. Bacteriol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Smith, T.J., Hill, K.K., Foley, B.T., Detter, J.C., Munk, A.C., Bruce, D.C., Doggett, N.A., Smith, L.A., Marks, J.D., and Xie, G. (2007). Analysis of the neurotoxin complex genes in Clostridium botulinum A1-A4 and B1 strains: BoNT\/A3, \/Ba4 and \/B1 clusters are located within plasmids. PLoS ONE, 2.","DOI":"10.1371\/journal.pone.0001271"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5450","DOI":"10.1128\/IAI.73.9.5450-5457.2005","article-title":"Sequence Variation within Botulinum Neurotoxin Serotypes Impacts Antibody Binding and Neutralization","volume":"73","author":"Smith","year":"2005","journal-title":"Infect. Immun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.jmb.2006.07.040","article-title":"A structural perspective of the sequence variability within botulinum neurotoxin subtypes A1-A4","volume":"362","author":"Arndt","year":"2006","journal-title":"J. Mol. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"8643","DOI":"10.1128\/JB.00784-07","article-title":"Sequencing the botulinum neurotoxin gene and related genes in Clostridium botulinum type E strains reveals orfx3 and a novel type E neurotoxin subtype","volume":"189","author":"Chen","year":"2007","journal-title":"J. Bacteriol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Carter, A.T., Paul, C.J., Mason, D.R., Twine, S.M., Alston, M.J., Logan, S.M., Austin, J.W., and Peck, M.W. (2009). Independent evolution of neurotoxin and flagellar genetic loci in proteolytic Clostridium botulinum. BMC Genom., 10.","DOI":"10.1186\/1471-2164-10-115"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S0065-2911(09)05503-9","article-title":"Biology and Genomic Analysis of Clostridium botulinum","volume":"Volume 55","author":"Poole","year":"2009","journal-title":"Advances in Microbial Physiology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.fm.2010.03.005","article-title":"Clostridium botulinum in the post-genomic era","volume":"28","author":"Peck","year":"2011","journal-title":"Food Microbiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.3389\/fmicb.2016.01702","article-title":"Diversity of the Germination Apparatus in Clostridium botulinum Groups I, II, III, and IV","volume":"7","author":"Brunt","year":"2016","journal-title":"Front. Microbiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1111\/j.1442-200X.1996.tb03542.x","article-title":"The first case of type B infant botulism in Japan","volume":"38","author":"Kakinuma","year":"1996","journal-title":"Acta Paediatr. Jpn. Overseas Ed."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4811","DOI":"10.1128\/IAI.66.10.4811-4816.1998","article-title":"Characterization of Clostridium botulinum type B neurotoxin associated with infant botulism in japan","volume":"66","author":"Kozaki","year":"1998","journal-title":"Infect. Immun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S0167-4781(02)00537-7","article-title":"Sequence of the gene for Clostridium botulinum type B neurotoxin associated with infant botulism, expression of the C-terminal half of heavy chain and its binding activity","volume":"1625","author":"Ihara","year":"2003","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1111\/j.1348-0421.2012.00441.x","article-title":"Stability of toxigenicity in proteolytic Clostridium botulinum type B upon serial passage","volume":"56","author":"Umeda","year":"2012","journal-title":"Microbiol. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Stringer, S.C., Carter, A.T., Webb, M.D., Wachnicka, E., Crossman, L.C., Sebaihia, M., and Peck, M.W. (2013). Genomic and physiological variability within Group II (non-proteolytic) Clostridium botulinum. BMC Genom., 14.","DOI":"10.1186\/1471-2164-14-333"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1093\/gbe\/evt068","article-title":"The type F6 neurotoxin gene cluster locus of group II Clostridium botulinum has evolved by successive disruption of two different ancestral precursors","volume":"5","author":"Carter","year":"2013","journal-title":"Genome Biol. Evol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4718","DOI":"10.1128\/JCM.42.10.4718-4725.2004","article-title":"Type C botulism due to toxic feed affecting 52,000 farmed foxes and minks in Finland","volume":"42","author":"Nevas","year":"2004","journal-title":"J. Clin. Microbiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1136\/vr.162.13.409","article-title":"Major outbreak of suspected botulism in a dairy herd in the Republic of Ireland","volume":"162","author":"Sharpe","year":"2008","journal-title":"Vet. Rec."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e01105-15","DOI":"10.1128\/genomeA.01105-15","article-title":"Draft Genome Sequences of 17 French Clostridium botulinum Group III Strains","volume":"3","author":"Woudstra","year":"2015","journal-title":"Genome Announc."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1093\/infdis\/143.1.22","article-title":"Isolation of Clostridium botulinum type G and identification of type G botulinal toxin in humans: Report of five sudden unexpected deaths","volume":"143","author":"Sonnabend","year":"1981","journal-title":"J. Infect. Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1128\/jcm.26.10.2191-2192.1988","article-title":"Genetic confirmation of identities of neurotoxigenic Clostridium baratii and Clostridium butyricum implicated as agents of infant botulism","volume":"26","author":"Suen","year":"1988","journal-title":"J. Clin. Microbiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1093\/gbe\/evw101","article-title":"Diversity of Group I and II Clostridium botulinum Strains from France Including Recently Identified Subtypes","volume":"8","author":"Mazuet","year":"2016","journal-title":"Genome Biol. Evol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.mib.2005.08.006","article-title":"Genomics of clostridial pathogens: Implication of extrachromosomal elements in pathogenicity","volume":"8","year":"2005","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.febslet.2014.12.018","article-title":"Botulinum neurotoxin homologs in non-Clostridium species","volume":"589","author":"Mansfield","year":"2015","journal-title":"FEBS Lett."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1002\/1873-3468.12969","article-title":"Identification of a novel botulinum neurotoxin gene cluster in Enterococcus","volume":"592","author":"Brunt","year":"2018","journal-title":"FEBS Lett."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1038\/s41598-018-37647-8","article-title":"Bioinformatic discovery of a toxin family in Chryseobacterium piperi with sequence similarity to botulinum neurotoxins","volume":"9","author":"Mansfield","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"30257","DOI":"10.1038\/srep30257","article-title":"The first non Clostridial botulinum-like toxin cleaves VAMP within the juxtamembrane domain","volume":"6","author":"Zornetta","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.chom.2017.12.018","article-title":"Identification of a botulinum neurotoxin-like toxin in a commensal strain of Enterococcus faecium","volume":"23","author":"Zhang","year":"2018","journal-title":"Cell Host Microbe"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Brunt, J., van Vliet, A.H.M., Carter, A.T., Stringer, S.C., Amar, C., Grant, K.A., Godbole, G., and Peck, M.W. (2020). Diversity of the Genomes and Neurotoxins of Strains of Clostridium botulinum Group I and Clostridium sporogenes Associated with Foodborne, Infant and Wound Botulism. Toxins, 12.","DOI":"10.3390\/toxins12090586"},{"key":"ref_62","unstructured":"Padda, I.S., and Tadi, P. (2021). Botulinum Toxin. StatPearls, StatPearls Publishing."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1080\/14737175.2021.1958678","article-title":"Exploring the role of botulinum toxin in critical care","volume":"21","author":"Hafeez","year":"2021","journal-title":"Expert Rev. Neurother."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1111\/j.1365-2672.1995.tb03135.x","article-title":"In situ characterization of Clostridium botulinum neurotoxin synthesis and export","volume":"79","author":"Call","year":"1995","journal-title":"J. Appl. Bacteriol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"683","DOI":"10.3390\/toxins2040683","article-title":"Bacterial Toxins and the Nervous System: Neurotoxins and Multipotential Toxins Interacting with Neuronal Cells","volume":"2","author":"Popoff","year":"2010","journal-title":"Toxins"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1038\/2338","article-title":"Crystal structure of botulinum neurotoxin type A and implications for toxicity","volume":"5","author":"Lacy","year":"1998","journal-title":"Nat. Struct. Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/0163-7258(82)90061-4","article-title":"Clostridium botulinum toxins","volume":"19","author":"Sakaguchi","year":"1982","journal-title":"Pharmacol. Ther."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"566908","DOI":"10.3389\/fmicb.2021.566908","article-title":"The Distinctive Evolution of orfX Clostridium parabotulinum Strains and Their Botulinum Neurotoxin Type A and F Gene Clusters Is Influenced by Environmental Factors and Gene Interactions via Mobile Genetic Elements","volume":"12","author":"Smith","year":"2021","journal-title":"Front. Microbiol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1128\/iai.64.5.1589-1594.1996","article-title":"Molecular composition of Clostridium botulinum type A progenitor toxins","volume":"64","author":"Inoue","year":"1996","journal-title":"Infect. Immun."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Montecucco, C. (1995). Molecular Genetics of Clostridial Neurotoxins. Clostridial Neurotoxins: The Molecular Pathogenesis of Tetanus and Botulism, Springer. Current Topics in Microbiology and Immunology.","DOI":"10.1007\/978-3-642-85173-5"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/0014-5793(95)01241-5","article-title":"Molecular characterization of two forms of nontoxic-nonhemagglutinin components of Clostridium botulinum type A progenitor toxins","volume":"376","author":"Fujita","year":"1995","journal-title":"FEBS Lett."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"4091","DOI":"10.1128\/JCM.02392-12","article-title":"Toxin Detection in Patients\u2019 Sera by Mass Spectrometry during Two Outbreaks of Type A Botulism in France","volume":"50","author":"Mazuet","year":"2012","journal-title":"J. Clin. Microbiol."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Kalb, S.R., Baudys, J., Smith, T.J., Smith, L.A., and Barr, J.R. (2017). Characterization of Hemagglutinin Negative Botulinum Progenitor Toxins. Toxins, 9.","DOI":"10.3390\/toxins9060193"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Gustafsson, R., Zhang, S., Masuyer, G., Dong, M., and Stenmark, P. (2018). Crystal Structure of Botulinum Neurotoxin A2 in Complex with the Human Protein Receptor SV2C Reveals Plasticity in Receptor Binding. Toxins, 10.","DOI":"10.3390\/toxins10040153"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.toxicon.2017.10.012","article-title":"The hypothetical protein P47 of Clostridium botulinum E1 strain Beluga has a structural topology similar to bactericidal\/permeability-increasing protein","volume":"147","author":"Lam","year":"2018","journal-title":"Toxicon Off. J. Int. Soc. Toxinol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"3781","DOI":"10.1002\/1873-3468.12889","article-title":"Crystal structures of OrfX2 and P47 from a Botulinum neurotoxin OrfX-type gene cluster","volume":"591","author":"Gustafsson","year":"2017","journal-title":"FEBS Lett."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/978-3-642-33570-9_3","article-title":"Uptake of Botulinum Neurotoxin in the Intestine","volume":"Volume 364","author":"Rummel","year":"2012","journal-title":"Botulinum Neurotoxins"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"5630","DOI":"10.1073\/pnas.1222139110","article-title":"Molecular assembly of botulinum neurotoxin progenitor complexes","volume":"110","author":"Benefield","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.resmic.2014.10.010","article-title":"Genomes, neurotoxins and biology of Clostridium botulinum Group I and Group II","volume":"166","author":"Carter","year":"2015","journal-title":"Res. Microbiol."},{"key":"ref_80","first-page":"21","article-title":"Molecular characterization of type E Clostridium botulinum and comparison to other types of Clostridium botulinum","volume":"1395","author":"Li","year":"1998","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"4478","DOI":"10.1128\/AEM.71.8.4478-4486.2005","article-title":"Characterization of botulinum progenitor toxins by mass spectrometry","volume":"71","author":"Hines","year":"2005","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1128\/AEM.02817-14","article-title":"Immunoprecipitation of native botulinum neurotoxin complexes from Clostridium botulinum subtype A strains","volume":"81","author":"Lin","year":"2015","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_83","unstructured":"Singh, B.R., and Zhang, Z. (2011). Proteins within the Type E Botulinum Neurotoxin Complex. (7,981,432), U.S. Patent ."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1023\/A:1022590514771","article-title":"A protease-resistant novel hemagglutinin purified from type A Clostridium botulinum","volume":"17","author":"Fu","year":"1998","journal-title":"J. Protein Chem."},{"key":"ref_85","first-page":"239","article-title":"Hemagglutinin binding mediated protection of botulinum neurotoxin from proteolysis","volume":"7","author":"Sharma","year":"1998","journal-title":"J. Nat. Toxins"},{"key":"ref_86","first-page":"21","article-title":"Assembly and Function of the Botulinum Neurotoxin Progenitor Complex","volume":"364","author":"Gu","year":"2013","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1124\/jpet.105.092213","article-title":"Visualization of binding and transcytosis of botulinum toxin by human intestinal epithelial cells","volume":"315","author":"Ahsan","year":"2005","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1124\/jpet.104.066845","article-title":"Structural Features of the Botulinum Neurotoxin Molecule That Govern Binding and Transcytosis across Polarized Human Intestinal Epithelial Cells","volume":"310","author":"Maksymowych","year":"2004","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"21950","DOI":"10.1074\/jbc.273.34.21950","article-title":"Binding and transcytosis of botulinum neurotoxin by polarized human colon carcinoma cells","volume":"273","author":"Maksymowych","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_90","first-page":"375","article-title":"Receptor-mediated transcytosis of botulinum neurotoxin A through intestinal cell monolayers","volume":"10","author":"Couesnon","year":"2008","journal-title":"Cell. Microbiol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.1462-5822.2008.01253.x","article-title":"Differential entry of botulinum neurotoxin A into neuronal and intestinal cells","volume":"11","author":"Couesnon","year":"2009","journal-title":"Cell. Microbiol."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Couesnon, A., Molg\u00f3, J., Connan, C., and Popoff, M.R. (2012). Preferential entry of botulinum neurotoxin A Hc domain through intestinal crypt cells and targeting to cholinergic neurons of the mouse intestine. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002583"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"3841","DOI":"10.1099\/00221287-143-12-3841","article-title":"The haemagglutinin of Clostridium botulinum type C progenitor toxin plays an essential role in binding of toxin to the epithelial cells of guinea pig small intestine, leading to the efficient absorption of the toxin","volume":"143","author":"Fujinaga","year":"1997","journal-title":"Microbiology"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Ghosal, K.J., Patel, K., Singh, B.R., and Hale, M.L. (2018). Role of critical elements in botulinum neurotoxin complex in toxin routing across intestinal and bronchial barriers. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0199524"},{"key":"ref_95","unstructured":"Mukkavalli, S.V. (2016). Cellular and Molecular Mechanism of Bio-Enhancing Properties of Biological Macromolecules and Herbal Nanoparticles: A Dissertation in BIOMEDICAL Engineering and Biotechnology. [Ph.D. Thesis, University of Massachusetts Dartmouth]."},{"key":"ref_96","first-page":"355","article-title":"The HA proteins of botulinum toxin disrupt intestinal epithelial intercellular junctions to increase toxin absorption","volume":"10","author":"Matsumura","year":"2008","journal-title":"Cell. Microbiol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1099\/mic.0.021246-0","article-title":"Disruption of the epithelial barrier by botulinum haemagglutinin (HA) proteins\u2014Differences in cell tropism and the mechanism of action between HA proteins of types A or B, and HA proteins of type C","volume":"155","author":"Jin","year":"2009","journal-title":"Microbiol. Read. Engl."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1083\/jcb.200910119","article-title":"Botulinum hemagglutinin disrupts the intercellular epithelial barrier by directly binding E-cadherin","volume":"189","author":"Sugawara","year":"2010","journal-title":"J. Cell Biol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/82_2017_50","article-title":"Uptake of Clostridial Neurotoxins into Cells and Dissemination","volume":"Volume 406","author":"Barth","year":"2017","journal-title":"Uptake and Trafficking of Protein Toxins"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"4305","DOI":"10.1128\/IAI.00405-09","article-title":"Antibody protection against botulinum neurotoxin intoxication in mice","volume":"77","author":"Cheng","year":"2009","journal-title":"Infect. Immun."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"5569","DOI":"10.1021\/ac4008418","article-title":"Substrates and controls for the quantitative detection of active botulinum neurotoxin in protease-containing samples","volume":"85","author":"Bagramyan","year":"2013","journal-title":"Anal. Chem."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.toxicon.2017.10.020","article-title":"Translocation and dissemination of botulinum neurotoxin from the intestinal tract","volume":"147","author":"Fujinaga","year":"2018","journal-title":"Toxicon"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1111\/cmi.12502","article-title":"Translocation and dissemination to target neurons of botulinum neurotoxin type B in the mouse intestinal wall","volume":"18","author":"Connan","year":"2016","journal-title":"Cell. Microbiol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.toxicon.2013.02.014","article-title":"The life history of a botulinum toxin molecule","volume":"68","author":"Simpson","year":"2013","journal-title":"Toxicon"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Poulain, B., and Popoff, M. (2019). Why Are Botulinum Neurotoxin-Producing Bacteria So Diverse and Botulinum Neurotoxins So Toxic?. Toxins, 11.","DOI":"10.3390\/toxins11010034"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"3689","DOI":"10.1523\/JNEUROSCI.0375-08.2008","article-title":"Long-Distance Retrograde Effects of Botulinum Neurotoxin A","volume":"28","author":"Antonucci","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1017\/S0033583500003292","article-title":"Structure and function of tetanus and botulinum neurotoxins","volume":"28","author":"Montecucco","year":"1995","journal-title":"Q. Rev. Biophys."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1038\/77900","article-title":"Intimate details of the most poisonous poison","volume":"7","author":"Singh","year":"2000","journal-title":"Nat. Struct. Biol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1038\/nsb1097-788","article-title":"Structure of the receptor binding fragment HC of tetanus neurotoxin","volume":"4","author":"Umland","year":"1997","journal-title":"Nat. Struct. Biol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/78005","article-title":"Structural analysis of the catalytic and binding sites of Clostridium botulinum neurotoxin B","volume":"7","author":"Swaminathan","year":"2000","journal-title":"Nat. Struct. Biol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2058","DOI":"10.1038\/ncomms3058","article-title":"Structure of dual receptor binding to botulinum neurotoxin B","volume":"4","author":"Berntsson","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Davies, J.R., Liu, S.M., and Acharya, K.R. (2018). Variations in the Botulinum Neurotoxin Binding Domain and the Potential for Novel Therapeutics. Toxins, 10.","DOI":"10.3390\/toxins10100421"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/0968-0004(86)90282-3","article-title":"How do tetanus and botulinum toxins bind to neuronal membranes?","volume":"11","author":"Montecucco","year":"1986","journal-title":"Trends Biochem. Sci."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1111\/j.1471-4159.2009.06093.x","article-title":"Cell entry strategy of clostridial neurotoxins","volume":"109","author":"Binz","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"4467","DOI":"10.1111\/j.1742-4658.2011.08183.x","article-title":"Molecular structures and functional relationships in clostridial neurotoxins","volume":"278","author":"Swaminathan","year":"2011","journal-title":"FEBS J."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"40806","DOI":"10.1074\/jbc.M112.404244","article-title":"Botulinum Neurotoxin Serotype C Associates with Dual Ganglioside Receptors to Facilitate Cell Entry","volume":"287","author":"Karalewitz","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/S0014-5793(00)01954-2","article-title":"Structure-based sequence alignment for the \u03b2-trefoil subdomain of the clostridial neurotoxin family provides residue level information about the putative ganglioside binding site","volume":"482","author":"Ginalski","year":"2000","journal-title":"FEBS Lett."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1942","DOI":"10.1111\/j.1471-4159.2009.06298.x","article-title":"Botulinum neurotoxins C, E and F bind gangliosides via a conserved binding site prior to stimulation-dependent uptake with botulinum neurotoxin F utilising the three isoforms of SV2 as second receptor","volume":"110","author":"Rummel","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1042\/BJ20101042","article-title":"Botulinum neurotoxin serotype D attacks neurons via two carbohydrate-binding sites in a ganglioside-dependent manner","volume":"431","author":"Strotmeier","year":"2010","journal-title":"Biochem. J."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1016\/j.biochi.2011.11.004","article-title":"The receptor binding domain of botulinum neurotoxin serotype C binds phosphoinositides","volume":"94","author":"Zhang","year":"2012","journal-title":"Biochimie"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"35164","DOI":"10.1074\/jbc.M507596200","article-title":"Binding of Clostridium botulinum type C and D neurotoxins to ganglioside and phospholipid. Novel insights into the receptor for clostridial neurotoxins","volume":"280","author":"Tsukamoto","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.bbrc.2009.01.037","article-title":"The N-terminal half of the receptor domain of botulinum neurotoxin A binds to microdomains of the plasma membrane","volume":"380","author":"Muraro","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1126\/science.1123654","article-title":"SV2 is the protein receptor for botulinum neurotoxin A","volume":"312","author":"Dong","year":"2006","journal-title":"Science"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1016\/j.febslet.2006.02.074","article-title":"The synaptic vesicle protein 2C mediates the uptake of botulinum neurotoxin A into phrenic nerves","volume":"580","author":"Mahrhold","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1083\/jcb.200305098","article-title":"Synaptotagmins I and II mediate entry of botulinum neurotoxin B into cells","volume":"162","author":"Dong","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1073\/pnas.0609713104","article-title":"Identification of the protein receptor binding site of botulinum neurotoxins B and G proves the double-receptor concept","volume":"104","author":"Rummel","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1016\/j.jmb.2010.02.041","article-title":"Crystal structure of the botulinum neurotoxin type G binding domain: Insight into cell surface binding","volume":"397","author":"Stenmark","year":"2010","journal-title":"J. Mol. Biol."},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Peng, L., Tepp, W.H., Johnson, E.A., and Dong, M. (2011). Botulinum Neurotoxin D Uses Synaptic Vesicle Protein SV2 and Gangliosides as Receptors. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1002008"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"5226","DOI":"10.1091\/mbc.e08-07-0765","article-title":"Glycosylated SV2A and SV2B Mediate the Entry of Botulinum Neurotoxin E into Neurons","volume":"19","author":"Dong","year":"2008","journal-title":"Mol. Biol. Cell"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"5631","DOI":"10.1021\/bi9002138","article-title":"Glycosylated SV2 and Gangliosides as Dual Receptors for Botulinum Neurotoxin Serotype F","volume":"48","author":"Fu","year":"2009","journal-title":"Biochemistry"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"30865","DOI":"10.1074\/jbc.M403945200","article-title":"Synaptotagmins I and II act as nerve cell receptors for botulinum neurotoxin G","volume":"279","author":"Rummel","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"5200","DOI":"10.1021\/bi100412v","article-title":"Structural analysis of botulinum neurotoxin type G receptor binding","volume":"49","author":"Schmitt","year":"2010","journal-title":"Biochemistry"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"3930","DOI":"10.1021\/bi4003502","article-title":"Botulinum neurotoxin G binds synaptotagmin-II in a mode similar to that of serotype B: Tyrosine 1186 and lysine 1191 cause its lower affinity","volume":"52","author":"Willjes","year":"2013","journal-title":"Biochemistry"},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Yao, G., Lam, K.-H., Perry, K., Weisemann, J., Rummel, A., and Jin, R. (2017). Crystal Structure of the Receptor-Binding Domain of Botulinum Neurotoxin Type HA, Also Known as Type FA or H. Toxins, 9.","DOI":"10.2210\/pdb5v38\/pdb"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/j.tim.2004.08.002","article-title":"Presynaptic receptor arrays for clostridial neurotoxins","volume":"12","author":"Montecucco","year":"2004","journal-title":"Trends Microbiol."},{"key":"ref_136","doi-asserted-by":"crossref","unstructured":"Yeh, F.L., Dong, M., Yao, J., Tepp, W.H., Lin, G., Johnson, E.A., and Chapman, E.R. (2010). SV2 mediates entry of tetanus neurotoxin into central neurons. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1001207"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"13310","DOI":"10.1073\/pnas.93.23.13310","article-title":"Synaptic vesicle endocytosis mediates the entry of tetanus neurotoxin into hippocampal neurons","volume":"93","author":"Matteoli","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1111\/j.1471-4159.1987.tb09994.x","article-title":"A study of the mechanism of internalisation of tetanus toxin by primary mouse spinal cord cultures","volume":"49","author":"Parton","year":"1987","journal-title":"J. Neurochem."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1523\/JNEUROSCI.06-05-01443.1986","article-title":"Characterization of the binding and internalization of tetanus toxin in a neuroblastoma hybrid cell line","volume":"6","author":"Staub","year":"1986","journal-title":"J. Neurosci."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"2715","DOI":"10.1242\/jcs.112.16.2715","article-title":"Functional characterisation of tetanus and botulinum neurotoxins binding domains","volume":"112","author":"Lalli","year":"1999","journal-title":"J. Cell Sci."},{"key":"ref_141","first-page":"256","article-title":"Inhibition of vacuolar adenosine triphosphatase antagonizes the effects of clostridial neurotoxins but not phospholipase A2 neurotoxins","volume":"269","author":"Simpson","year":"1994","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"2342","DOI":"10.1046\/j.1471-4159.1994.63062342.x","article-title":"Bafilomycin A1 inhibits the action of tetanus toxin in spinal cord neurons in cell culture","volume":"63","author":"Williamson","year":"1994","journal-title":"J. Neurochem."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"13397","DOI":"10.1038\/srep13397","article-title":"Structural analysis of Clostridium botulinum neurotoxin type D as a platform for the development of targeted secretion inhibitors","volume":"5","author":"Masuyer","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.jmb.2008.12.027","article-title":"Domain organization in Clostridium botulinum neurotoxin type E is unique: Its implication in faster translocation","volume":"386","author":"Kumaran","year":"2009","journal-title":"J. Mol. Biol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.toxicon.2013.01.007","article-title":"Molecular dissection of botulinum neurotoxin reveals interdomain chaperone function","volume":"75","author":"Fischer","year":"2013","journal-title":"Toxicon Off. J. Int. Soc. Toxinol."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"17987","DOI":"10.1073\/pnas.0509035102","article-title":"Oxidizing potential of endosomes and lysosomes limits intracellular cleavage of disulfide-based antibody-drug conjugates","volume":"102","author":"Austin","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1007\/s10930-006-9028-1","article-title":"Botulinum neurotoxin light chain refolds at endosomal pH for its translocation","volume":"25","author":"Cai","year":"2006","journal-title":"Protein J."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1016\/j.bbapap.2015.05.013","article-title":"Structural and Functional Analysis of Botulinum Neurotoxin subunits for pH-dependent Membrane Channel Formation and Translocation","volume":"1854","author":"Chellappan","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s10930-017-9744-8","article-title":"High Yield Preparation of Functionally Active Catalytic-Translocation Domain Module of Botulinum Neurotoxin Type A That Exhibits Uniquely Different Enzyme Kinetics","volume":"36","author":"Dhaliwal","year":"2017","journal-title":"Protein J."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.15252\/embr.201744500","article-title":"Tetanus neurotoxin: Conformational plasticity as an adaptive strategy","volume":"18","author":"Montal","year":"2017","journal-title":"EMBO Rep."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.toxicon.2017.10.008","article-title":"The travel diaries of tetanus and botulinum neurotoxins","volume":"147","author":"Surana","year":"2018","journal-title":"Toxicon"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1128\/IAI.00057-12","article-title":"Tetanus Toxin and Botulinum Toxin A Utilize Unique Mechanisms To Enter Neurons of the Central Nervous System","volume":"80","author":"Blum","year":"2012","journal-title":"Infect. Immun."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"42336","DOI":"10.1074\/jbc.M506750200","article-title":"Tetanus toxin is transported in a novel neuronal compartment characterized by a specialized pH regulation","volume":"280","author":"Bohnert","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"31394","DOI":"10.1074\/jbc.M103517200","article-title":"Recombinant forms of tetanus toxin engineered for examining and exploiting neuronal trafficking pathways","volume":"276","author":"Li","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"10120","DOI":"10.1073\/pnas.152266799","article-title":"Retrograde trans-synaptic transfer of green fluorescent protein allows the genetic mapping of neuronal circuits in transgenic mice","volume":"99","author":"Maskos","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_156","first-page":"5035","article-title":"Novel chimeras of botulinum and tetanus neurotoxins yield insights into their distinct sites of neuroparalysis","volume":"26","author":"Wang","year":"2012","journal-title":"FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1128\/IAI.01539-13","article-title":"Entry of a recombinant, full-length, atoxic tetanus neurotoxin into Neuro-2a cells","volume":"82","author":"Blum","year":"2014","journal-title":"Infect. Immun."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.neuron.2006.08.018","article-title":"Rab5 and Rab7 Control Endocytic Sorting along the Axonal Retrograde Transport Pathway","volume":"52","author":"Deinhardt","year":"2006","journal-title":"Neuron"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.semcdb.2013.10.004","article-title":"Signalling endosomes in axonal transport: Travel updates on the molecular highway","volume":"27","author":"Schmieg","year":"2014","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/978-1-0716-0585-1_20","article-title":"In Vivo Imaging of Anterograde and Retrograde Axonal Transport in Rodent Peripheral Nerves","volume":"2143","author":"Sleigh","year":"2020","journal-title":"Methods Mol. Biol."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.neuint.2012.05.001","article-title":"Botulinum toxin\u2019s axonal transport from periphery to the spinal cord","volume":"61","author":"Matak","year":"2012","journal-title":"Neurochem. Int."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1111\/j.1600-0854.2012.01369.x","article-title":"Botulinum neurotoxin A impairs neurotransmission following retrograde transynaptic transport","volume":"13","author":"Restani","year":"2012","journal-title":"Traffic Cph. Den."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"15650","DOI":"10.1523\/JNEUROSCI.2618-11.2011","article-title":"Evidence for anterograde transport and transcytosis of botulinum neurotoxin A (BoNT\/A)","volume":"31","author":"Restani","year":"2011","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_164","doi-asserted-by":"crossref","unstructured":"Restani, L., Giribaldi, F., Manich, M., Bercsenyi, K., Menendez, G., Rossetto, O., Caleo, M., and Schiavo, G. (2012). Botulinum neurotoxins A and E undergo retrograde axonal transport in primary motor neurons. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1003087"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"47","DOI":"10.2174\/187152607780090667","article-title":"Strategies to design inhibitors of Clostridium botulinum neurotoxins","volume":"7","author":"Cai","year":"2007","journal-title":"Infect. Disord. Drug Targets"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1517\/17460441.2014.884066","article-title":"Current strategies for designing antidotes against botulinum neurotoxins","volume":"9","author":"Patel","year":"2014","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"978","DOI":"10.3390\/toxins2050978","article-title":"The zinc-dependent protease activity of the botulinum neurotoxins","volume":"2","author":"Lebeda","year":"2010","journal-title":"Toxins"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/0022-5193(79)90141-3","article-title":"Toxicity of botulinum toxin: A stoichiometric model for the locus of its extraordinary potency and persistence at the neuromuscular junction","volume":"77","author":"Hanig","year":"1979","journal-title":"J. Theor. Biol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1074\/jbc.M209821200","article-title":"Evaluation of the therapeutic usefulness of botulinum neurotoxin B, C1, E, and F compared with the long lasting type A. Basis for distinct durations of inhibition of exocytosis in central neurons","volume":"278","author":"Foran","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"S53","DOI":"10.1002\/mds.20010","article-title":"Different types of botulinum toxin in humans","volume":"19","author":"Eleopra","year":"2004","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"2697","DOI":"10.1111\/j.1460-9568.2007.05529.x","article-title":"Neuromuscular paralysis and recovery in mice injected with botulinum neurotoxins A and C","volume":"25","author":"Morbiato","year":"2007","journal-title":"Eur. J. Neurosci."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1212\/WNL.53.7.1439","article-title":"Safety and efficacy of NeuroBloc (Botulinum toxin type B) in type A-responsive cervical dystonia","volume":"53","author":"Brashear","year":"1999","journal-title":"Neurology"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"116516","DOI":"10.1016\/j.jns.2019.116516","article-title":"Safety and pharmacodynamics of a novel recombinant botulinum toxin E (rBoNT-E): Results of a phase 1 study in healthy male subjects compared with abobotulinumtoxinA (Dysport\u00ae)","volume":"407","author":"Pons","year":"2019","journal-title":"J. Neurol. Sci."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1124\/pr.116.012658","article-title":"Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology","volume":"69","author":"Pirazzini","year":"2017","journal-title":"Pharmacol. Rev."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"13004","DOI":"10.1073\/pnas.0605420103","article-title":"Quantification of protein half-lives in the budding yeast proteome","volume":"103","author":"Belle","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"5275","DOI":"10.1021\/pr101183k","article-title":"Systems-wide proteomic analysis in mammalian cells reveals conserved, functional protein turnover","volume":"10","author":"Cambridge","year":"2011","journal-title":"J. Proteome Res."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"14508","DOI":"10.1073\/pnas.1006551107","article-title":"Analysis of proteome dynamics in the mouse brain","volume":"107","author":"Price","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_178","doi-asserted-by":"crossref","unstructured":"Gardner, A.P., and Barbieri, J.T. (2018). Light Chain Diversity among the Botulinum Neurotoxins. Toxins, 10.","DOI":"10.3390\/toxins10070268"},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/365160a0","article-title":"Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25","volume":"365","author":"Blasi","year":"1993","journal-title":"Nature"},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1038\/359832a0","article-title":"Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin","volume":"359","author":"Schiavo","year":"1992","journal-title":"Nature"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"10566","DOI":"10.1074\/jbc.270.18.10566","article-title":"Botulinum neurotoxin type C cleaves a single Lys-Ala bond within the carboxyl-terminal region of syntaxins","volume":"270","author":"Schiavo","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1111\/j.1348-0421.2012.00434.x","article-title":"Specificity of botulinum protease for human VAMP family proteins","volume":"56","author":"Yamamoto","year":"2012","journal-title":"Microbiol. Immunol."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"12764","DOI":"10.1016\/S0021-9258(18)99941-2","article-title":"Cleavage of members of the synaptobrevin\/VAMP family by types D and F botulinal neurotoxins and tetanus toxin","volume":"269","author":"Yamasaki","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1016\/S0021-9258(17)42071-0","article-title":"Proteolysis of SNAP-25 by types E and A botulinal neurotoxins","volume":"269","author":"Binz","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/0014-5793(93)80448-4","article-title":"Botulinum neurotoxins serotypes A and E cleave SNAP-25 at distinct COOH-terminal peptide bonds","volume":"335","author":"Schiavo","year":"1993","journal-title":"FEBS Lett."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"20213","DOI":"10.1016\/S0021-9258(17)31976-2","article-title":"Botulinum G neurotoxin cleaves VAMP\/synaptobrevin at a single Ala-Ala peptide bond","volume":"269","author":"Schiavo","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1006\/bbrc.1994.1526","article-title":"Botulinum neurotoxin type G proteolyses the Ala81-Ala82 bond of rat synaptobrevin 2","volume":"200","author":"Yamasaki","year":"1994","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"16554","DOI":"10.1073\/pnas.1008302107","article-title":"Targeting botulinum neurotoxin persistence by the ubiquitin-proteasome system","volume":"107","author":"Tsai","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_189","first-page":"179","article-title":"Persistence of Botulinum neurotoxin inactivation of nerve function","volume":"364","author":"Shoemaker","year":"2013","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_190","first-page":"3294","article-title":"Recruitment of septin cytoskeletal proteins by botulinum toxin A protease determines its remarkable stability","volume":"127","author":"Vagin","year":"2014","journal-title":"J. Cell Sci."},{"key":"ref_191","doi-asserted-by":"crossref","unstructured":"Whitemarsh, R.C.M., Tepp, W.H., Johnson, E.A., and Pellett, S. (2014). Persistence of Botulinum Neurotoxin A Subtypes 1-5 in Primary Rat Spinal Cord Cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0090252"},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"20227","DOI":"10.1074\/jbc.271.34.20227","article-title":"SNAP-25 is required for a late postdocking step in Ca2+-dependent exocytosis","volume":"271","author":"Banerjee","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"15388","DOI":"10.1073\/pnas.0805377105","article-title":"The role of the C terminus of the SNARE protein SNAP-25 in fusion pore opening and a model for fusion pore mechanics","volume":"105","author":"Fang","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"S23","DOI":"10.1002\/mds.20006","article-title":"Is the light chain subcellular localization an important factor in botulinum toxin duration of action?","volume":"19","author":"Ho","year":"2004","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"3208","DOI":"10.1073\/pnas.0400229101","article-title":"Plasma membrane localization signals in the light chain of botulinum neurotoxin","volume":"101","author":"Steward","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"4136","DOI":"10.1128\/iai.58.12.4136-4141.1990","article-title":"An intact interchain disulfide bond is required for the neurotoxicity of tetanus toxin","volume":"58","author":"Schiavo","year":"1990","journal-title":"Infect. Immun."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"20838","DOI":"10.1016\/S0021-9258(19)36861-9","article-title":"A role for the interchain disulfide or its participating thiols in the internalization of botulinum neurotoxin A revealed by a toxin derivative that binds to ecto-acceptors and inhibits transmitter release intracellularly","volume":"268","author":"Poulain","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"29604","DOI":"10.1074\/jbc.M703619200","article-title":"Crucial role of the disulfide bridge between botulinum neurotoxin light and heavy chains in protease translocation across membranes","volume":"282","author":"Fischer","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1111\/j.1462-5822.2011.01654.x","article-title":"Double anchorage to the membrane and intact inter-chain disulfide bond are required for the low pH induced entry of tetanus and botulinum neurotoxins into neurons","volume":"13","author":"Pirazzini","year":"2011","journal-title":"Cell. Microbiol."},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/372415a0","article-title":"SNARE motif and neurotoxins","volume":"372","author":"Rossetto","year":"1994","journal-title":"Nature"},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1038\/nature03123","article-title":"Substrate recognition strategy for botulinum neurotoxin serotype A","volume":"432","author":"Breidenbach","year":"2004","journal-title":"Nature"},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1038\/nsmb.1626","article-title":"Mode of VAMP substrate recognition and inhibition of Clostridium botulinum neurotoxin F","volume":"16","author":"Agarwal","year":"2009","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1023\/A:1010952025677","article-title":"Enzymatic autocatalysis of botulinum A neurotoxin light chain","volume":"20","author":"Ahmed","year":"2001","journal-title":"J. Protein Chem."},{"key":"ref_204","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/nrmicro3295","article-title":"Botulinum neurotoxins: Genetic, structural and mechanistic insights","volume":"12","author":"Rossetto","year":"2014","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_205","doi-asserted-by":"crossref","first-page":"20353","DOI":"10.1074\/jbc.271.34.20353","article-title":"Structural determinants of the specificity for synaptic vesicle-associated membrane protein\/synaptobrevin of tetanus and botulinum type B and G neurotoxins","volume":"271","author":"Pellizzari","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_206","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0014-5793(97)01328-8","article-title":"Botulinum neurotoxin types A and E require the SNARE motif in SNAP-25 for proteolysis","volume":"418","author":"Washbourne","year":"1997","journal-title":"FEBS Lett."},{"key":"ref_207","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1016\/j.toxicon.2009.11.017","article-title":"The identification and biochemical characterization of drug-like compounds that inhibit botulinum neurotoxin serotype A endopeptidase activity","volume":"55","author":"Cai","year":"2010","journal-title":"Toxicon Off. J. Int. Soc. Toxinol."},{"key":"ref_208","doi-asserted-by":"crossref","first-page":"28036","DOI":"10.1074\/jbc.272.44.28036","article-title":"Structural changes are associated with soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor complex formation","volume":"272","author":"Fasshauer","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_209","doi-asserted-by":"crossref","first-page":"9374","DOI":"10.1021\/bi010362z","article-title":"Differential roles of developmentally distinct SNAP-25 isoforms in the neurotransmitter release process","volume":"40","author":"Puffer","year":"2001","journal-title":"Biochemistry"},{"key":"ref_210","doi-asserted-by":"crossref","first-page":"5801","DOI":"10.1021\/acs.jpcb.0c02817","article-title":"Botulinum Endopeptidase: SAXS Experiments and MD Simulations Reveal Extended Solution Structures That Account for Its Biochemical Properties","volume":"124","author":"Kumar","year":"2020","journal-title":"J. Phys. Chem. B"},{"key":"ref_211","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.bmc.2004.10.026","article-title":"Conformational sampling of the botulinum neurotoxin serotype A light chain: Implications for inhibitor binding","volume":"13","author":"Burnett","year":"2005","journal-title":"Bioorg. Med. Chem."},{"key":"ref_212","doi-asserted-by":"crossref","first-page":"15327","DOI":"10.1021\/bi011350g","article-title":"Role of the disulfide cleavage induced molten globule state of type a botulinum neurotoxin in its endopeptidase activity","volume":"40","author":"Cai","year":"2001","journal-title":"Biochemistry"},{"key":"ref_213","doi-asserted-by":"crossref","first-page":"2510","DOI":"10.1021\/bi902096r","article-title":"Molecular basis of activation of endopeptidase activity of botulinum neurotoxin type E","volume":"49","author":"Kukreja","year":"2010","journal-title":"Biochemistry"},{"key":"ref_214","doi-asserted-by":"crossref","first-page":"39346","DOI":"10.1074\/jbc.M508463200","article-title":"Biologically active novel conformational state of botulinum, the most poisonous poison","volume":"280","author":"Kukreja","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_215","doi-asserted-by":"crossref","first-page":"129933","DOI":"10.1016\/j.bbagen.2021.129933","article-title":"Botulinum neurotoxin inhibitor binding dynamics and kinetics relevant for drug design","volume":"1865","author":"Patel","year":"2021","journal-title":"Biochim. Biophys. Acta Gen. Subj."},{"key":"ref_216","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/j.bbapap.2014.02.012","article-title":"Differential role of molten globule and protein folding in distinguishing unique features of botulinum neurotoxin","volume":"1844","author":"Kumar","year":"2014","journal-title":"Biochim. Biophys. Acta BBA-Proteins Proteomics"},{"key":"ref_217","doi-asserted-by":"crossref","first-page":"5736","DOI":"10.1021\/bi8001067","article-title":"Catalytic Features of the Botulinum Neurotoxin A Light Chain Revealed by High Resolution Structure of an Inhibitory Peptide Complex","volume":"47","author":"Silvaggi","year":"2008","journal-title":"Biochemistry"},{"key":"ref_218","doi-asserted-by":"crossref","first-page":"8884","DOI":"10.1038\/s41598-018-26764-z","article-title":"A novel role of C-terminus in introducing a functionally flexible structure critical for the biological activity of botulinum neurotoxin","volume":"8","author":"Feltrup","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_219","doi-asserted-by":"crossref","first-page":"6903","DOI":"10.1021\/bi990086c","article-title":"Enhancement of the endopeptidase activity of botulinum neurotoxin by its associated proteins and dithiothreitol","volume":"38","author":"Cai","year":"1999","journal-title":"Biochemistry"},{"key":"ref_220","doi-asserted-by":"crossref","first-page":"4693","DOI":"10.1021\/bi0025363","article-title":"A correlation between differential structural features and the degree of endopeptidase activity of type A botulinum neurotoxin in aqueous solution","volume":"40","author":"Cai","year":"2001","journal-title":"Biochemistry"},{"key":"ref_221","doi-asserted-by":"crossref","first-page":"4791","DOI":"10.1021\/bi0355544","article-title":"Enhancement of the endopeptidase activity of purified botulinum neurotoxins A and E by an isolated component of the native neurotoxin associated proteins","volume":"43","author":"Sharma","year":"2004","journal-title":"Biochemistry"},{"key":"ref_222","doi-asserted-by":"crossref","first-page":"24777","DOI":"10.1074\/jbc.M703446200","article-title":"A novel subunit structure of Clostridium botulinum serotype D toxin complex with three extended arms","volume":"282","author":"Hasegawa","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_223","doi-asserted-by":"crossref","unstructured":"Lee, K., Gu, S., Jin, L., Le, T.T.N., Cheng, L.W., Strotmeier, J., Kruel, A.M., Yao, G., Perry, K., and Rummel, A. (2013). Structure of a bimodular botulinum neurotoxin complex provides insights into its oral toxicity. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003690"},{"key":"ref_224","doi-asserted-by":"crossref","first-page":"24223","DOI":"10.1074\/jbc.M113.451286","article-title":"The C Terminus of the Catalytic Domain of Type A Botulinum Neurotoxin May Facilitate Product Release from the Active Site","volume":"288","author":"Mizanur","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_225","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.bbapap.2014.12.004","article-title":"Resolution of sub-nanosecond motions in botulinum neurotoxin endopeptidase: An evidence of internal flexibility","volume":"1854","author":"Kumar","year":"2015","journal-title":"Biochim. Biophys. Acta BBA-Proteins Proteomics"},{"key":"ref_226","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/BF00183530","article-title":"Molten globule intermediates and protein folding","volume":"19","author":"Christensen","year":"1991","journal-title":"Eur. Biophys. J. EBJ"},{"key":"ref_227","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S0065-3233(08)60546-X","article-title":"Molten globule and protein folding","volume":"47","author":"Ptitsyn","year":"1995","journal-title":"Adv. Protein Chem."},{"key":"ref_228","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/352036a0","article-title":"Chaperonin-mediated protein folding at the surface of groEL through a \u2019molten globule\u2019-like intermediate","volume":"352","author":"Martin","year":"1991","journal-title":"Nature"},{"key":"ref_229","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.sbi.2012.11.004","article-title":"Molten globules, entropy-driven conformational change and protein folding","volume":"23","author":"Baldwin","year":"2013","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_230","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1042\/BC20050082","article-title":"Bacterial protein toxins and lipids: Pore formation or toxin entry into cells","volume":"98","author":"Geny","year":"2006","journal-title":"Biol. Cell"},{"key":"ref_231","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1111\/j.1742-4658.2009.07511.x","article-title":"Accessibility changes within diphtheria toxin T domain when in the functional molten globule state, as determined using hydrogen\/deuterium exchange measurements","volume":"277","author":"Man","year":"2010","journal-title":"FEBS J."},{"key":"ref_232","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1126\/science.284.5416.955","article-title":"Interaction of diphtheria toxin T domain with molten globule-like proteins and its implications for translocation","volume":"284","author":"Ren","year":"1999","journal-title":"Science"},{"key":"ref_233","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.mam.2009.06.003","article-title":"Membrane translocation by anthrax toxin","volume":"30","author":"Collier","year":"2009","journal-title":"Mol. Aspects Med."},{"key":"ref_234","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1134\/S1068162014040098","article-title":"Molecular model of anthrax toxin translocation into target-cells","volume":"40","author":"Noskov","year":"2014","journal-title":"Russ. J. Bioorganic Chem."},{"key":"ref_235","doi-asserted-by":"crossref","unstructured":"Felix, I., Lomada, S.K., Barth, H., and Wieland, T. (2020). Bacillus anthracis\u2019 PA63 Delivers the Tumor Metastasis Suppressor Protein NDPK-A\/NME1 into Breast Cancer Cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21093295"},{"key":"ref_236","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.jmb.2004.09.067","article-title":"Acid-induced unfolding of the amino-terminal domains of the lethal and edema factors of anthrax toxin","volume":"344","author":"Krantz","year":"2004","journal-title":"J. Mol. Biol."},{"key":"ref_237","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0092-8674(01)00198-2","article-title":"Cytolysin-mediated translocation (CMT): A functional equivalent of type III secretion in gram-positive bacteria","volume":"104","author":"Madden","year":"2001","journal-title":"Cell"},{"key":"ref_238","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/978-94-017-8881-6_9","article-title":"Multifaceted Activity of Listeriolysin O, the Cholesterol-Dependent Cytolysin of Listeria monocytogenes","volume":"80","author":"Seveau","year":"2014","journal-title":"Subcell. Biochem."},{"key":"ref_239","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/978-94-017-8881-6_5","article-title":"Perfringolysin O Structure and Mechanism of Pore Formation as a Paradigm for Cholesterol-Dependent Cytolysins","volume":"80","author":"Johnson","year":"2014","journal-title":"Subcell. Biochem."},{"key":"ref_240","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.cell.2005.02.033","article-title":"Structural Basis of Pore Formation by the Bacterial Toxin Pneumolysin","volume":"121","author":"Tilley","year":"2005","journal-title":"Cell"},{"key":"ref_241","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/nrmicro.2015.3","article-title":"Pore-forming toxins: Ancient, but never really out of fashion","volume":"14","author":"Peraro","year":"2016","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_242","doi-asserted-by":"crossref","first-page":"8655","DOI":"10.1074\/jbc.271.15.8655","article-title":"Partial C-terminal unfolding is required for channel formation by staphylococcal alpha-toxin","volume":"271","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_243","doi-asserted-by":"crossref","first-page":"45","DOI":"10.3109\/09687689709068435","article-title":"Membrane insertion: The strategies of toxins (Review)","volume":"14","author":"Lesieur","year":"1997","journal-title":"Mol. Membr. Biol."},{"key":"ref_244","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1016\/j.molcel.2011.09.022","article-title":"Structural Instability Tuning as a Regulatory Mechanism in Protein-Protein Interactions","volume":"44","author":"Chen","year":"2011","journal-title":"Mol. Cell"},{"key":"ref_245","doi-asserted-by":"crossref","first-page":"12860","DOI":"10.1073\/pnas.0404109101","article-title":"An enzymatic molten globule: Efficient coupling of folding and catalysis","volume":"101","author":"Vamvaca","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_246","doi-asserted-by":"crossref","first-page":"11727","DOI":"10.1073\/pnas.2003138117","article-title":"Cell entry mechanisms of SARS-CoV-2","volume":"117","author":"Shang","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_247","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1016\/j.bbapap.2010.01.017","article-title":"Understanding Protein Non-Folding","volume":"1804","author":"Uversky","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_248","doi-asserted-by":"crossref","unstructured":"Kuroda, Y., Endo, S., and Nakamura, H. (2020). How a Novel Scientific Concept Was Coined the \u201cMolten Globule State\u201d. Biomolecules, 10.","DOI":"10.3390\/biom10020269"},{"key":"ref_249","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/0165-022X(80)90050-0","article-title":"Multidimensional spectroscopic data correlation in the conformation transition of biological macromolecules","volume":"2","author":"Wada","year":"1980","journal-title":"J. Biochem. Biophys. Methods"},{"key":"ref_250","doi-asserted-by":"crossref","first-page":"105101","DOI":"10.1063\/5.0039194","article-title":"Unfolding bovine \u03b1-lactalbumin with T-jump: Characterizing disordered intermediates via time-resolved x-ray solution scattering and molecular dynamics simulations","volume":"154","author":"Hsu","year":"2021","journal-title":"J. Chem. Phys."},{"key":"ref_251","doi-asserted-by":"crossref","first-page":"4035","DOI":"10.1021\/acs.jmedchem.5b01684","article-title":"Role of Molecular Dynamics and Related Methods in Drug Discovery","volume":"59","author":"Masetti","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_252","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1007\/978-1-0716-1154-8_14","article-title":"Molecular Dynamics Simulation Techniques as Tools in Drug Discovery and Pharmacology: A Focus on Allosteric Drugs","volume":"2253","author":"Platania","year":"2021","journal-title":"Methods Mol. Biol."},{"key":"ref_253","doi-asserted-by":"crossref","first-page":"545","DOI":"10.4155\/fmc.16.9","article-title":"Advanced molecular dynamics simulation methods for kinase drug discovery","volume":"8","author":"Ziada","year":"2016","journal-title":"Future Med. Chem."},{"key":"ref_254","doi-asserted-by":"crossref","first-page":"e1500527","DOI":"10.1126\/sciadv.1500527","article-title":"A phylogenomic data-driven exploration of viral origins and evolution","volume":"1","author":"Nasir","year":"2015","journal-title":"Sci. Adv."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/9\/11\/2206\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:21:48Z","timestamp":1760167308000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/9\/11\/2206"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,23]]},"references-count":254,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["microorganisms9112206"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms9112206","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,23]]}}}