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

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. Surpris...

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Bibliographic Details
Published inStructure (London) Vol. 16; no. 10
Main Authors 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.
Format Journal Article
LanguageEnglish
Published United States 28.05.2009
Subjects
CLEAVAGE
CRYSTAL STRUCTURE
DATA
INDUCTION
INHIBITION
LETHAL MUTATIONS
MATERIALS SCIENCE
MOLECULES
Other,OTHER
RESIDUES
SUBSTRATES
TOXINS
WATER
ZINC
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Summary: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.
Bibliography:SLAC-REPRINT-2009-353
USDOE
AC02-76SF00515
ISSN:0969-2126
1878-4186