{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T02:01:13Z","timestamp":1788400873328,"version":"build-2803163510"},"reference-count":45,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,3,20]],"date-time":"2025-03-20T00:00:00Z","timestamp":1742428800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2014Next Generation EU","award":["LX22NPO5103"],"award-info":[{"award-number":["LX22NPO5103"]}]},{"name":"European Union\u2014Next Generation EU","award":["LM2023042"],"award-info":[{"award-number":["LM2023042"]}]},{"name":"European Union\u2014Next Generation EU","award":["CZ.02.01.01\/00\/23_015\/0008175"],"award-info":[{"award-number":["CZ.02.01.01\/00\/23_015\/0008175"]}]},{"name":"European Union\u2014Next Generation EU","award":["846688"],"award-info":[{"award-number":["846688"]}]},{"name":"European Union\u2014Next Generation EU","award":["R01AI158612"],"award-info":[{"award-number":["R01AI158612"]}]},{"name":"European Union\u2014Next Generation EU","award":["R21AI146387"],"award-info":[{"award-number":["R21AI146387"]}]},{"name":"European Union\u2014Next Generation EU","award":["R21AI133393"],"award-info":[{"award-number":["R21AI133393"]}]},{"name":"European Union\u2014Next Generation EU","award":["R21AI171824"],"award-info":[{"award-number":["R21AI171824"]}]},{"name":"MEYS CR","award":["LX22NPO5103"],"award-info":[{"award-number":["LX22NPO5103"]}]},{"name":"MEYS CR","award":["LM2023042"],"award-info":[{"award-number":["LM2023042"]}]},{"name":"MEYS CR","award":["CZ.02.01.01\/00\/23_015\/0008175"],"award-info":[{"award-number":["CZ.02.01.01\/00\/23_015\/0008175"]}]},{"name":"MEYS CR","award":["846688"],"award-info":[{"award-number":["846688"]}]},{"name":"MEYS CR","award":["R01AI158612"],"award-info":[{"award-number":["R01AI158612"]}]},{"name":"MEYS CR","award":["R21AI146387"],"award-info":[{"award-number":["R21AI146387"]}]},{"name":"MEYS CR","award":["R21AI133393"],"award-info":[{"award-number":["R21AI133393"]}]},{"name":"MEYS CR","award":["R21AI171824"],"award-info":[{"award-number":["R21AI171824"]}]},{"name":"European Regional Development Fund-Project \u201cInnovation of Czech Infrastructure for Integrative Structural Biology\u201d","award":["LX22NPO5103"],"award-info":[{"award-number":["LX22NPO5103"]}]},{"name":"European Regional Development Fund-Project \u201cInnovation of Czech Infrastructure for Integrative Structural Biology\u201d","award":["LM2023042"],"award-info":[{"award-number":["LM2023042"]}]},{"name":"European Regional Development Fund-Project \u201cInnovation of Czech Infrastructure for Integrative Structural Biology\u201d","award":["CZ.02.01.01\/00\/23_015\/0008175"],"award-info":[{"award-number":["CZ.02.01.01\/00\/23_015\/0008175"]}]},{"name":"European Regional Development Fund-Project \u201cInnovation of Czech Infrastructure for Integrative Structural Biology\u201d","award":["846688"],"award-info":[{"award-number":["846688"]}]},{"name":"European Regional Development Fund-Project \u201cInnovation of Czech Infrastructure for Integrative Structural Biology\u201d","award":["R01AI158612"],"award-info":[{"award-number":["R01AI158612"]}]},{"name":"European Regional Development Fund-Project \u201cInnovation of Czech Infrastructure for Integrative Structural Biology\u201d","award":["R21AI146387"],"award-info":[{"award-number":["R21AI146387"]}]},{"name":"European Regional Development Fund-Project \u201cInnovation of Czech Infrastructure for Integrative Structural Biology\u201d","award":["R21AI133393"],"award-info":[{"award-number":["R21AI133393"]}]},{"name":"European Regional Development Fund-Project \u201cInnovation of Czech Infrastructure for Integrative Structural Biology\u201d","award":["R21AI171824"],"award-info":[{"award-number":["R21AI171824"]}]},{"name":"European Union\u2019s Horizon 2020 research and innovation programm","award":["LX22NPO5103"],"award-info":[{"award-number":["LX22NPO5103"]}]},{"name":"European Union\u2019s Horizon 2020 research and innovation programm","award":["LM2023042"],"award-info":[{"award-number":["LM2023042"]}]},{"name":"European Union\u2019s Horizon 2020 research and innovation programm","award":["CZ.02.01.01\/00\/23_015\/0008175"],"award-info":[{"award-number":["CZ.02.01.01\/00\/23_015\/0008175"]}]},{"name":"European Union\u2019s Horizon 2020 research and innovation programm","award":["846688"],"award-info":[{"award-number":["846688"]}]},{"name":"European Union\u2019s Horizon 2020 research and innovation programm","award":["R01AI158612"],"award-info":[{"award-number":["R01AI158612"]}]},{"name":"European Union\u2019s Horizon 2020 research and innovation programm","award":["R21AI146387"],"award-info":[{"award-number":["R21AI146387"]}]},{"name":"European Union\u2019s Horizon 2020 research and innovation programm","award":["R21AI133393"],"award-info":[{"award-number":["R21AI133393"]}]},{"name":"European Union\u2019s Horizon 2020 research and innovation programm","award":["R21AI171824"],"award-info":[{"award-number":["R21AI171824"]}]},{"name":"NIH","award":["LX22NPO5103"],"award-info":[{"award-number":["LX22NPO5103"]}]},{"name":"NIH","award":["LM2023042"],"award-info":[{"award-number":["LM2023042"]}]},{"name":"NIH","award":["CZ.02.01.01\/00\/23_015\/0008175"],"award-info":[{"award-number":["CZ.02.01.01\/00\/23_015\/0008175"]}]},{"name":"NIH","award":["846688"],"award-info":[{"award-number":["846688"]}]},{"name":"NIH","award":["R01AI158612"],"award-info":[{"award-number":["R01AI158612"]}]},{"name":"NIH","award":["R21AI146387"],"award-info":[{"award-number":["R21AI146387"]}]},{"name":"NIH","award":["R21AI133393"],"award-info":[{"award-number":["R21AI133393"]}]},{"name":"NIH","award":["R21AI171824"],"award-info":[{"award-number":["R21AI171824"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The 20S proteasome, a critical component of the ubiquitin\u2013proteasome system, plays a central role in regulating protein degradation in eukaryotic cells. Marizomib (MZB), also known as salinosporamide A, is a natural \u03b3-lactam-\u03b2-lactone compound derived from Salinispora tropica and is a potent 20S proteasome covalent inhibitor with demonstrated anticancer properties. Its broad-spectrum inhibition of all three proteasome subunits and its ability to cross the blood\u2013brain barrier has made it a promising therapeutic candidate for glioblastoma. In addition to this, MZB also demonstrates significant inhibition against the 20S proteasome of Trichomonas vaginalis (Tv20S), a protozoan parasite, suggesting its potential for parasitic treatments. Here, we present the cryo-EM structure of the human 20S proteasome in complex with MZB at 2.55 \u00c5 resolution. This structure reveals the binding mode of MZB to all six catalytic subunits within the two \u03b2-rings of the 20S proteasome, providing a detailed molecular understanding of its irreversible inhibitory mechanism. These findings enhance the therapeutic potential of MZB for both cancer and parasitic diseases at the molecular level and highlight marine-derived natural products in targeting the proteasome for therapeutic applications.<\/jats:p>","DOI":"10.3390\/molecules30061386","type":"journal-article","created":{"date-parts":[[2025,3,20]],"date-time":"2025-03-20T07:59:54Z","timestamp":1742457594000},"page":"1386","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Structural Insights into Salinosporamide a Mediated Inhibition of the Human 20S Proteasome"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7636-700X","authenticated-orcid":false,"given":"Hagen","family":"S\u00fclzen","sequence":"first","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo namesti 2, 16610 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavla","family":"Fajtova","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo namesti 2, 16610 Prague, Czech Republic"},{"name":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5695-0409","authenticated-orcid":false,"given":"Anthony J.","family":"O\u2019Donoghue","sequence":"additional","affiliation":[{"name":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA"},{"name":"Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3868-5714","authenticated-orcid":false,"given":"Jan","family":"Silhan","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo namesti 2, 16610 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9652-4065","authenticated-orcid":false,"given":"Evzen","family":"Boura","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo namesti 2, 16610 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1002\/anie.200390115","article-title":"Salinosporamide A: A highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus Salinospora","volume":"42","author":"Feling","year":"2003","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5005","DOI":"10.1128\/AEM.68.10.5005-5011.2002","article-title":"Widespread and Persistent Populations of a Major New Marine Actinomycete Taxon in Ocean Sediments","volume":"68","author":"Mincer","year":"2002","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1093\/neuonc\/noae053","article-title":"Marizomib for patients with newly diagnosed glioblastoma: A randomized phase 3 trial","volume":"26","author":"Roth","year":"2024","journal-title":"Neuro-Oncology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1093\/neuonc\/nov299","article-title":"Marizomib activity as a single agent in malignant gliomas: Ability to cross the blood-brain barrier","volume":"18","author":"Di","year":"2015","journal-title":"Neuro-Oncology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"18953","DOI":"10.1038\/srep18953","article-title":"Induction of cell death by the novel proteasome inhibitor marizomib in glioblastoma in vitro and in vivo","volume":"6","author":"Manton","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.3109\/10428194.2013.828351","article-title":"The proteasome: Mechanisms of biology and markers of activity and response to treatment in multiple myeloma","volume":"55","author":"Manasanch","year":"2014","journal-title":"Leuk. Lymphoma"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/s41467-019-14038-9","article-title":"Golgi organization is regulated by proteasomal degradation","volume":"11","author":"Benyair","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"12","DOI":"10.2183\/pjab.85.12","article-title":"The proteasome: Overview of structure and functions","volume":"85","author":"Tanaka","year":"2009","journal-title":"Proc. Jpn. Acad Ser. B Phys. Biol. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1146\/annurev.bi.65.070196.004101","article-title":"STRUCTURE AND FUNCTIONS OF THE 20S AND 26S PROTEASOMES","volume":"65","author":"Coux","year":"1996","journal-title":"Annu. Rev. Biochem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1101\/SQB.1995.060.01.055","article-title":"Structure and Function of the 20S Proteasome and of Its Regulatory Complexes","volume":"60","author":"Lupas","year":"1995","journal-title":"Cold Spring Harb. Symp. Quant. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1126\/science.7725097","article-title":"Crystal Structure of the 20S Proteasome from the Archaeon T. acidophilum at 3.4 \u00c5 Resolution","volume":"268","author":"Stock","year":"1995","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1021\/bi00057a022","article-title":"Evidence for the presence of five distinct proteolytic components in the pituitary multicatalytic proteinase complex. Properties of two components cleaving bonds on the carboxyl side of branched chain and small neutral amino acids","volume":"32","author":"Orlowski","year":"1993","journal-title":"Biochemistry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1916","DOI":"10.1002\/med.21502","article-title":"Proteasome-mediated proteostasis: Novel medicinal and pharmacological strategies for diseases","volume":"38","author":"Mishra","year":"2018","journal-title":"Med. Res. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.bbamcr.2013.08.012","article-title":"Regulation of proteasome activity in health and disease","volume":"1843","author":"Schmidt","year":"2014","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Cell Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1126\/science.7732382","article-title":"Inhibition of Proteasome Activities and Subunit-Specific Amino-Terminal Threonine Modification by Lactacystin","volume":"268","author":"Fenteany","year":"1995","journal-title":"Science"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2850","DOI":"10.2174\/156802611798281320","article-title":"Proteasome Structure, Function, and Lessons Learned from Beta-Lactone Inhibitors","volume":"11","author":"Groll","year":"2011","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.1021\/jm048995+","article-title":"Structure\u2013Activity Relationship Studies of Salinosporamide A (NPI-0052), a Novel Marine Derived Proteasome Inhibitor","volume":"48","author":"Macherla","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5136","DOI":"10.1021\/ja058320b","article-title":"Crystal Structures of Salinosporamide A (NPI-0052) and B (NPI-0047) in Complex with the 20S Proteasome Reveal Important Consequences of \u03b2-Lactone Ring Opening and a Mechanism for Irreversible Binding","volume":"128","author":"Groll","year":"2006","journal-title":"J. Am. Chem. Soc."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8621","DOI":"10.1038\/s41467-024-53022-w","article-title":"Structural elucidation of recombinant Trichomonas vaginalis 20S proteasome bound to covalent inhibitors","volume":"15","author":"Silhan","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Prudhomme, J., McDaniel, E., Ponts, N., Bertani, S., Fenical, W., Jensen, P., and Le Roch, K. (2008). Marine Actinomycetes: A New Source of Compounds against the Human Malaria Parasite. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0002335"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1107\/S2059798318009324","article-title":"New tools for the analysis and validation of cryo-EM maps and atomic models","volume":"74","author":"Afonine","year":"2018","journal-title":"Acta Crystallogr. Sect. D Struct. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3217","DOI":"10.1038\/s41467-023-39031-1","article-title":"Improvement of cryo-EM maps by simultaneous local and non-local deep learning","volume":"14","author":"He","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1021\/cr0502504","article-title":"20S Proteasome and Its Inhibitors: Crystallographic Knowledge for Drug Development","volume":"107","author":"Borissenko","year":"2007","journal-title":"Chem. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e5225","DOI":"10.1002\/pro.5225","article-title":"Distinct substrate specificities of the three catalytic subunits of the Trichomonas vaginalis proteasome","volume":"33","author":"Fajtova","year":"2024","journal-title":"Protein Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/0092-8674(94)90396-4","article-title":"The ubiquitin-proteasome proteolytic pathway","volume":"79","author":"Ciechanover","year":"1994","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.ccr.2005.10.013","article-title":"A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib","volume":"8","author":"Chauhan","year":"2005","journal-title":"Cancer Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1053\/j.seminoncol.2018.01.004","article-title":"Proteasome inhibitors: Structure and function","volume":"44","author":"Nunes","year":"2017","journal-title":"Semin. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.trsl.2018.03.002","article-title":"Next-generation proteasome inhibitors for cancer therapy","volume":"198","author":"Park","year":"2018","journal-title":"Transl. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"101100","DOI":"10.1016\/j.blre.2023.101100","article-title":"Proteasome inhibition in combination with immunotherapies: State-of-the-Art in multiple myeloma","volume":"61","author":"Kegyes","year":"2023","journal-title":"Blood Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5259","DOI":"10.7150\/thno.42705","article-title":"Marizomib suppresses triple-negative breast cancer via proteasome and oxidative phosphorylation inhibition","volume":"10","author":"Raninga","year":"2020","journal-title":"Theranostics"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Zhang, Z., Zhang, S., Lin, B., Wang, Q., Nie, X., and Shi, Y. (2022). Combined treatment of marizomib and cisplatin modulates cervical cancer growth and invasion and enhances antitumor potential in vitro and in vivo. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.974573"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.freeradbiomed.2016.12.007","article-title":"Proteasome inhibitors in cancer therapy: Treatment regimen and peripheral neuropathy as a side effect","volume":"103","author":"Kaplan","year":"2017","journal-title":"Free Radic. Biol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"44989","DOI":"10.1021\/acsomega.4c04564","article-title":"Evaluating Antimalarial Proteasome Inhibitors for Efficacy in Babesia Blood Stage Cultures","volume":"9","author":"Robbertse","year":"2024","journal-title":"ACS Omega"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Eadsforth, T.C., Torrie, L.S., Rowland, P., Edgar, E.V., MacLean, L.M., Paterson, C., Robinson, D.A., Shepherd, S.M., Thomas, J., and Thomas, M.G. (2024). Pharmacological and structural understanding of the Trypanosoma cruzi proteasome provides key insights for developing site-specific inhibitors. J. Biol. Chem., 301.","DOI":"10.1016\/j.jbc.2024.108049"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.cbi.2011.08.005","article-title":"Specific and prolonged proteasome inhibition dictates apoptosis induction by marizomib and its analogs","volume":"194","author":"Miller","year":"2011","journal-title":"Chem. Interact."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/nmeth.4169","article-title":"cryoSPARC: Algorithms for rapid unsupervised cryo-EM structure determination","volume":"14","author":"Punjani","year":"2017","journal-title":"Nat. Methods"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6173","DOI":"10.1038\/s41467-021-26427-0","article-title":"The 20S as a stand-alone proteasome in cells can degrade the ubiquitin tag","volume":"12","author":"Sahu","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1002\/pro.3943","article-title":"UCSF ChimeraX: Structure visualization for researchers, educators, and developers","volume":"30","author":"Pettersen","year":"2020","journal-title":"Protein Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1107\/S2059798318006551","article-title":"Real-space refinement in PHENIX for cryo-EM and crystallography","volume":"74","author":"Afonine","year":"2018","journal-title":"Acta Crystallogr. Sect. D Struct. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1107\/S2059798319011471","article-title":"Macromolecular structure determination using X-rays, neutrons and electrons: Recent developments in Phenix","volume":"75","author":"Liebschner","year":"2019","journal-title":"Acta Crystallogr. Sect. D Struct. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1107\/S0907444910007493","article-title":"Features and development of Coot","volume":"66","author":"Emsley","year":"2010","journal-title":"Acta Crystallogr. Sect. D Biol. Crystallogr."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1107\/S2059798318002425","article-title":"ISOLDE: A physically realistic environment for model building into low-resolution electron-density maps","volume":"74","author":"Croll","year":"2018","journal-title":"Acta Crystallogr. Sect. D Struct. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1107\/S090744491200251X","article-title":"JLigand: A graphical tool for the CCP4 template-restraint library","volume":"68","author":"Lebedev","year":"2012","journal-title":"Acta Crystallogr. Sect. D Struct. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1002\/pro.3330","article-title":"MolProbity: More and better reference data for improved all-atom structure validation","volume":"27","author":"Williams","year":"2018","journal-title":"Protein Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.1021\/ci200227u","article-title":"LigPlot+: Multiple ligand\u2013protein interaction diagrams for drug discovery","volume":"51","author":"Laskowski","year":"2011","journal-title":"J. Chem. Inf. Model."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/6\/1386\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:57:07Z","timestamp":1760029027000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/6\/1386"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,20]]},"references-count":45,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["molecules30061386"],"URL":"https:\/\/doi.org\/10.3390\/molecules30061386","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.01.28.635221","asserted-by":"object"}]},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,20]]}}}