{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T09:30:33Z","timestamp":1768555833997,"version":"3.49.0"},"reference-count":41,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T00:00:00Z","timestamp":1670284800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006021","name":"DGA (Direction G\u00e9n\u00e9rale de l\u2019Armement)\/University of Aix-Marseille Ph.D. fellowship","doi-asserted-by":"publisher","award":["2020007"],"award-info":[{"award-number":["2020007"]}],"id":[{"id":"10.13039\/501100006021","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Botulinum neurotoxins are the deadliest microbial neurotoxins in humans, with a lethal dose of 1 ng\/kg. Incidentally, these neurotoxins are also widely used for medical and cosmetic purposes. However, little is known about the molecular mechanisms that control binding of botulinum neurotoxin type F1 (BoNT\/F1) to its membrane receptor, glycosylated human synaptic vesicle glycoprotein A (hSV2Ag). To elucidate these mechanisms, we performed a molecular dynamics simulation (MDS) study of initial binding kinetics of BoNT\/F1 to SV2A. Since this toxin also interacts with gangliosides, the simulations were performed at the periphery of a lipid raft in the presence of both SV2A and gangliosides. Our study suggested that interaction of BoNT\/F1 with SV2A is exclusively mediated by N-glycan moiety of SV2A, which interacts with aromatic residues Y898, Y910, F946, Y1059 and H1273 of this toxin. Thus, in contrast with botulinum neurotoxin A1 (BoNT\/A1), BoNT\/F1 does not interact with protein content of SV2A. We attributed this incapability to a barrage effect exerted by neurotoxin residues Y1132, Q1133 and K1134, which prevent formation of long-lasting intermolecular hydrogen bonds. We also provided structural elements that suggest that BoNT\/F1 uses the strategy of BoNT\/A1 combined with the strategy of botulinum neurotoxin type E to bind N-glycan of its glycoprotein receptor. Overall, our study opened a gate for design of a universal inhibitor aimed at disrupting N-glycan\u2013toxin interactions and for bioengineering of a BoNT\/F1 protein that may be able to bind protein content of synaptic vesicle glycoprotein for therapeutic purposes.<\/jats:p>","DOI":"10.3390\/biom12121821","type":"journal-article","created":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T02:18:48Z","timestamp":1670379528000},"page":"1821","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Structural Basis of Botulinum Toxin Type F Binding to Glycosylated Human SV2A: In Silico Studies at the Periphery of a Lipid Raft"],"prefix":"10.3390","volume":"12","author":[{"given":"Fodil","family":"Azzaz","sequence":"first","affiliation":[{"name":"Fodil Azzaz, INSERM U_1072, Facult\u00e9 de M\u00e9decine Nord, Bd Pierre Dramard, University of Aix-Marseille, 13015 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Didier","family":"Hilaire","sequence":"additional","affiliation":[{"name":"DGA (Direction G\u00e9n\u00e9rale de L\u2019armement)\u2014DGA Ma\u00eetrise NRBC, 91710 Vert le Petit, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8653-5521","authenticated-orcid":false,"given":"Jacques","family":"Fantini","sequence":"additional","affiliation":[{"name":"Fodil Azzaz, INSERM U_1072, Facult\u00e9 de M\u00e9decine Nord, Bd Pierre Dramard, University of Aix-Marseille, 13015 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.1212\/01.wnl.0000187127.92446.4c","article-title":"Adult botulism type F in the United States, 1981\u20132002","volume":"65","author":"Gupta","year":"2005","journal-title":"Neurology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1038\/sj.embor.7400796","article-title":"Entering neurons: Botulinum toxins and synaptic vesicle recycling","volume":"7","author":"Verderio","year":"2006","journal-title":"EMBO Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"14130","DOI":"10.1038\/ncomms14130","article-title":"Identification and characterization of a novel botulinum neurotoxin","volume":"8","author":"Zhang","year":"2017","journal-title":"Nat. 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