A Potent Peptidomimetic Inhibitor of Botulinum Neurotoxin Serotype a Has a Very Different Conformation Than SNAP-25 Substrate

Journal Article · Thu May 28 04:00:00 EDT 2009 · Structure 16:1588,2008

OSTI ID:953530

Zuniga, J E; Schmidt, J J; Fenn, T; Burnett, J C; Arac, D; Gussio, R; Stafford, R G; Badie, S S; Bavari, S; Brunger, A T

Botulinum neurotoxin serotype A is the most lethal of all known toxins. Here, we report the crystal structure, along with SAR data, of the zinc metalloprotease domain of BoNT/A bound to a potent peptidomimetic inhibitor (Ki = 41 nM) that resembles the local sequence of the SNAP-25 substrate. Surprisingly, the inhibitor adopts a helical conformation around the cleavage site, in contrast to the extended conformation of the native substrate. The backbone of the inhibitor's P1 residue displaces the putative catalytic water molecule and concomitantly interacts with the 'proton shuttle' E224. This mechanism of inhibition is aided by residue contacts in the conserved S1' pocket of the substrate binding cleft, and the induction of new hydrophobic pockets, which are not present in the apo form, especially for the P2' residue of the inhibitor. Our inhibitor is specific for BoNT/A as it does not inhibit other BoNT serotypes or thermolysin.

• Research Organization: Stanford Linear Accelerator Center (SLAC)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC02-76SF00515
• OSTI ID: 953530
• Report Number(s): SLAC-REPRINT-2009-353
• Journal Information: Structure 16:1588,2008, Journal Name: Structure 16:1588,2008 Journal Issue: 10 Vol. 16; ISSN 0969-2126
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
CLEAVAGE
CRYSTAL STRUCTURE
DATA
INDUCTION
INHIBITION
LETHAL MUTATIONS
MOLECULES
Other
OTHER
RESIDUES
SUBSTRATES
TOXINS
WATER
ZINC