Mode of VAMP Substrate Recognition and Inhibition of Clostridium botulinum Neurotoxin F

Journal Article · Thu Jan 01 04:00:00 EST 2009 · Nature Structural and Molecular Biology

DOI:https://doi.org/10.1038/nsmb.1626· OSTI ID:980343

Agarwal, R; Schmidt, J; Stafford, R; Swaminathan, S

Clostridium botulinum neurotoxins (BoNTs) cleave neuronal proteins responsible for neurotransmitter release, causing the neuroparalytic disease botulism. BoNT serotypes B, D, F and G cleave and inactivate vesicle-associated membrane protein (VAMP), each at a unique peptide bond. The specificity of BoNTs depends on the mode of substrate recognition. We have investigated the mechanism of substrate recognition of BoNT F by determining the crystal structures of its complex with two substrate-based inhibitors, VAMP 22-58/Gln58D-cysteine and 27-58/Gln58D-cysteine. The inhibitors bind to BoNT F in the canonical direction (as seen for BoNTs A and E substrates) but are positioned specifically via three major exosites away from the active site. The cysteine sulfur of the inhibitors interacts with the zinc and exists as sulfinic acid in the inhibitor VAMP 27-58/Gln58D-cysteine. Arg133 and Arg171, which form part of two separate exosites, are crucial for substrate binding and catalysis.

• Research Organization: Brookhaven National Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: Doe - Office Of Science
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 980343
• Report Number(s): BNL--93261-2010-JA
• Journal Information: Nature Structural and Molecular Biology, Journal Name: Nature Structural and Molecular Biology Journal Issue: 7 Vol. 16; ISSN 1072-8368
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
CATALYSIS
CLOSTRIDIUM BOTULINUM
CRYSTAL STRUCTURE
CYSTEINE
DISEASES
MEMBRANE PROTEINS
ORGANIC ACIDS
ORGANIC SULFUR COMPOUNDS
PEPTIDES
PROTEINS
SPECIFICITY
SUBSTRATES
SULFUR
ZINC
national synchrotron light source