4JRA
CRYSTAL STRUCTURE OF THE BOTULINUM NEUROTOXIN A RECEPTOR-BINDING DOMAIN IN COMPLEX WITH THE LUMINAL DOMAIN Of SV2C
Summary for 4JRA
| Entry DOI | 10.2210/pdb4jra/pdb |
| Descriptor | Botulinum neurotoxin type A, Synaptic vesicle glycoprotein 2C, CHLORIDE ION, ... (5 entities in total) |
| Functional Keywords | beta-helix, vesicles, lumen, toxin, hydrolase |
| Biological source | Clostridium botulinum More |
| Cellular location | Botulinum neurotoxin A light chain: Secreted. Botulinum neurotoxin A heavy chain: Secreted: P10845 Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane; Multi-pass membrane protein (By similarity): Q496J9 |
| Total number of polymer chains | 4 |
| Total formula weight | 135677.72 |
| Authors | Benoit, R.M.,Frey, D.,Wieser, M.M.,Jaussi, R.,Schertler, G.F.X.,Capitani, G.,Kammerer, R.A. (deposition date: 2013-03-21, release date: 2013-11-20, Last modification date: 2023-09-20) |
| Primary citation | Benoit, R.M.,Frey, D.,Hilbert, M.,Kevenaar, J.T.,Wieser, M.M.,Stirnimann, C.U.,McMillan, D.,Ceska, T.,Lebon, F.,Jaussi, R.,Steinmetz, M.O.,Schertler, G.F.,Hoogenraad, C.C.,Capitani, G.,Kammerer, R.A. Structural basis for recognition of synaptic vesicle protein 2C by botulinum neurotoxin A. Nature, 505:108-111, 2014 Cited by PubMed Abstract: Botulinum neurotoxin A (BoNT/A) belongs to the most dangerous class of bioweapons. Despite this, BoNT/A is used to treat a wide range of common medical conditions such as migraines and a variety of ocular motility and movement disorders. BoNT/A is probably best known for its use as an antiwrinkle agent in cosmetic applications (including Botox and Dysport). BoNT/A application causes long-lasting flaccid paralysis of muscles through inhibiting the release of the neurotransmitter acetylcholine by cleaving synaptosomal-associated protein 25 (SNAP-25) within presynaptic nerve terminals. Two types of BoNT/A receptor have been identified, both of which are required for BoNT/A toxicity and are therefore likely to cooperate with each other: gangliosides and members of the synaptic vesicle glycoprotein 2 (SV2) family, which are putative transporter proteins that are predicted to have 12 transmembrane domains, associate with the receptor-binding domain of the toxin. Recently, fibroblast growth factor receptor 3 (FGFR3) has also been reported to be a potential BoNT/A receptor. In SV2 proteins, the BoNT/A-binding site has been mapped to the luminal domain, but the molecular details of the interaction between BoNT/A and SV2 are unknown. Here we determined the high-resolution crystal structure of the BoNT/A receptor-binding domain (BoNT/A-RBD) in complex with the SV2C luminal domain (SV2C-LD). SV2C-LD consists of a right-handed, quadrilateral β-helix that associates with BoNT/A-RBD mainly through backbone-to-backbone interactions at open β-strand edges, in a manner that resembles the inter-strand interactions in amyloid structures. Competition experiments identified a peptide that inhibits the formation of the complex. Our findings provide a strong platform for the development of novel antitoxin agents and for the rational design of BoNT/A variants with improved therapeutic properties. PubMed: 24240280DOI: 10.1038/nature12732 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
Download full validation report
