{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T15:48:20Z","timestamp":1761061700296,"version":"build-2065373602"},"reference-count":40,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T00:00:00Z","timestamp":1661385600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"joint postgraduate studentship between University of Bath and Ipsen Bioinnovation Ltd."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Clostridium botulinum neurotoxin A (BoNT\/A) targets the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, by cleaving synaptosomal-associated protein of 25 kDa size (SNAP-25). Cleavage of SNAP-25 results in flaccid paralysis due to repression of synaptic transmission at the neuromuscular junction. This activity has been exploited to treat a range of diseases associated with hypersecretion of neurotransmitters, with formulations of BoNT\/A commercially available as therapeutics. Generally, BoNT activity is facilitated by three essential domains within the molecule, the cell binding domain (HC), the translocation domain (HN), and the catalytic domain (LC). The HC, which consists of an N-terminal (HCN) and a C-terminal (HCC) subdomain, is responsible for BoNT\u2019s high target specificity where it forms a dual-receptor complex with synaptic vesicle protein 2 (SV2) and a ganglioside receptor on the surface of motor neurons. In this study, we have determined the crystal structure of botulinum neurotoxin A6 cell binding domain (HC\/A6) in complex with GD1a and describe the interactions involved in ganglioside binding. We also present a new crystal form of wild type HC\/A6 (crystal form II) where a large \u2018hinge motion\u2019 between the HCN and HCC subdomains is observed. These structures, along with a comparison to the previously determined wild type crystal structure of HC\/A6 (crystal form I), reveals the degree of conformational flexibility exhibited by HC\/A6.<\/jats:p>","DOI":"10.3390\/ijms23179620","type":"journal-article","created":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T21:28:12Z","timestamp":1661462892000},"page":"9620","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Crystal Structures of the Clostridium botulinum Neurotoxin A6 Cell Binding Domain Alone and in Complex with GD1a Reveal Significant Conformational Flexibility"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5371-4283","authenticated-orcid":false,"given":"Kyle S.","family":"Gregory","sequence":"first","affiliation":[{"name":"Department of Life Sciences, University of Bath, Claverton Down, Bath BA2 7AY, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna R.","family":"Newell","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Bath, Claverton Down, Bath BA2 7AY, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Otsile O.","family":"Mojanaga","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Bath, Claverton Down, Bath BA2 7AY, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6359-0229","authenticated-orcid":false,"given":"Sai Man","family":"Liu","sequence":"additional","affiliation":[{"name":"Protein Sciences Department, Ipsen Bioinnovation Limited, 102 Park Drive, Milton Park, Abingdon OX14 4RY, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3009-4058","authenticated-orcid":false,"given":"K. Ravi","family":"Acharya","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Bath, Claverton Down, Bath BA2 7AY, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,25]]},"reference":[{"key":"ref_1","first-page":"489","article-title":"Botulinum Toxin: Bioweapon & Magic Drug","volume":"132","author":"Dhaked","year":"2010","journal-title":"Indian J. Med. Res."},{"key":"ref_2","first-page":"S73","article-title":"The Epidemiology of Foodborne Botulism Outbreaks: A Systematic Review","volume":"66","author":"Shankar","year":"2017","journal-title":"Clin. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Rasetti-Escargueil, C., and Popoff, M.R. (2019). Antibodies and Vaccines against Botulinum Toxins: Available Measures and Novel Approaches. 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