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

Abstract

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 (K(i)=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 by 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.

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Document Details

Document Type
Technical Report
Publication Date
Oct 07, 2008
Accession Number
ADA492122

Entities

People

  • Axel T. Brunger
  • Demet Arac
  • James C. Burnett
  • James J. Schmidt
  • Jorge E. Zuniga
  • Rick Gussio
  • Robert G. Stafford
  • Shirin S. Badie
  • Sina Bavari
  • Timothy Fenn

Organizations

  • Howard Hughes Medical Institute

Tags

Communities of Interest

  • Biomedical

DTIC Thesaurus Topics

  • Biochemistry
  • Chemistry
  • Crystal Structure
  • Crystals
  • Electron Density
  • Electrons
  • Hydrogen Bonds
  • Hydrophobic Properties
  • Inhibition
  • Molecules
  • Neurotoxins
  • Sequences
  • Small Molecules
  • Spine
  • Substrates
  • Three Dimensional
  • Toxins

Fields of Study

  • Biology
  • Chemistry

Readers

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