title: Identification of the synaptic vesicle glycoprotein 2 receptor binding site in botulinum neurotoxin A.
abstract: Botulinum neurotoxins (BoNTs) inhibit neurotransmitter release by hydrolysing SNARE proteins. The most important serotype BoNT/A employs the synaptic vesicle glycoprotein 2 (SV2) isoforms A-C as neuronal receptors. Here, we identified their binding site by blocking SV2 interaction using monoclonal antibodies with characterised epitopes within the cell binding domain (HC). The site is located on the backside of the conserved ganglioside binding pocket at the interface of the HCC and HCN subdomains. The dimension of the binding pocket was characterised in detail by site directed mutagenesis allowing the development of potent inhibitors as well as modifying receptor binding properties.
authors.affiliation: Institut für Toxikologie, OE 5340, Medizinische Hochschule Hannover, 30623 Hannover, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Strotmeier
authors.affiliation: Institut für Toxikologie, OE 5340, Medizinische Hochschule Hannover, 30623 Hannover, Germany; Institut für Biochemie, OE 4310, Medizinische Hochschule Hannover, 30623 Hannover, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mahrhold
authors.affiliation: Institut für Toxikologie, OE 5340, Medizinische Hochschule Hannover, 30623 Hannover, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Krez
authors.affiliation: Institut für Toxikologie, OE 5340, Medizinische Hochschule Hannover, 30623 Hannover, Germany.
authors.forename: Constantin
authors.initials: C
authors.lastname: Janzen
authors.affiliation: Department of Anesthesia, University of California, San Francisco, CA 94110, USA.
authors.forename: Jianlong
authors.initials: J
authors.lastname: Lou
authors.affiliation: Department of Anesthesia, University of California, San Francisco, CA 94110, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Marks
authors.affiliation: Institut für Biochemie, OE 4310, Medizinische Hochschule Hannover, 30623 Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Binz
authors.affiliation: Institut für Toxikologie, OE 5340, Medizinische Hochschule Hannover, 30623 Hannover, Germany. Electronic address: Rummel.Andreas@mh-hannover.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rummel
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D019274:Botulinum Toxins, Type A / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008562:Membrane Glycoproteins / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D009431:Neural Conduction / Q000187:drug effects; D009498:Neurotoxins / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D010791:Phrenic Nerve / Q000187:drug effects / Q000502:physiology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs
chemical_list: D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; C585899:SV2C protein, human; D019274:Botulinum Toxins, Type A
keywords: Botulinum neurotoxin A; Monoclonal antibody; Neutralisation; Protein receptor binding site; SV2