Publication Date:
2013-11-19
Description:
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 beta-helix that associates with BoNT/A-RBD mainly through backbone-to-backbone interactions at open beta-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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Benoit, Roger M -- Frey, Daniel -- Hilbert, Manuel -- Kevenaar, Josta T -- Wieser, Mara M -- Stirnimann, Christian U -- McMillan, David -- Ceska, Tom -- Lebon, Florence -- Jaussi, Rolf -- Steinmetz, Michel O -- Schertler, Gebhard F X -- Hoogenraad, Casper C -- Capitani, Guido -- Kammerer, Richard A -- England -- Nature. 2014 Jan 2;505(7481):108-11. doi: 10.1038/nature12732. Epub 2013 Nov 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Biomolecular Research, Paul Scherrer Institut, CH-5232 Villigen PSI, Switzerland. ; 1] Laboratory of Biomolecular Research, Paul Scherrer Institut, CH-5232 Villigen PSI, Switzerland [2]. ; 1] Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, The Netherlands [2]. ; Swiss Light Source, Paul Scherrer Institut, CH-5232 Villigen PSI, Switzerland. ; UCB Celltech, UCB Pharma, UCB NewMedicines, Slough SL1 4EN, UK. ; UCB Pharma, UCB NewMedicines, B-1420 Braine-L'Alleud, Belgium. ; 1] Laboratory of Biomolecular Research, Paul Scherrer Institut, CH-5232 Villigen PSI, Switzerland [2] Department of Biology, ETH Zurich, CH-8093 Zurich, Switzerland. ; Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24240280" target="_blank"〉PubMed〈/a〉
Keywords:
Binding Sites
;
Botulinum Toxins, Type A/*chemistry/*metabolism
;
Crystallography, X-Ray
;
Endocytosis/drug effects
;
HEK293 Cells
;
Humans
;
Membrane Glycoproteins/*chemistry/*metabolism
;
Models, Molecular
;
Neostriatum/cytology
;
Nerve Tissue Proteins/*chemistry/*metabolism
;
Neurons/drug effects
;
Peptide Fragments/chemistry/pharmacology
;
Structure-Activity Relationship
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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