Conformational sampling of the botulinum neurotoxin serotype a light chain: Implications for inhibitor binding

James C. Burnett, James J. Schmidt, Connor F. McGrath, Tam L. Nguyen, Ann R. Hermone, Rekha G. Panchal, Jonathan L. Vennerstrom, Krishna Kodukula, Daniel W. Zaharevitz, Rick Gussio, Sina Bavari

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


Molecular dynamics simulations were used to explore how residue motion in and around the botulinum neurotoxin serotype A light chain (BoNT/A LC) substrate binding cleft might affect inhibitor binding. Results from these studies indicate that surface loop reorientations toward the substrate binding cleft may facilitate small molecule binding by creating additional inhibitor-residue contacts. Based on molecular docking studies, our common pharmacophore model for BoNT/A LC inhibitors has been refined via the inclusion of these potential contact residues. Botulinum neurotoxins (BoNTs) are the most potent of the known biological toxins, and consequently are listed as category A biowarfare agents. Currently, the only treatments against BoNTs include preventative antitoxins and long-term supportive care. Consequently, there is an urgent need for therapeutics to counter these enzymes - post exposure. In a previous study, we identified a number of small, nonpeptidic lead inhibitors of BoNT serotype A light chain (BoNT/A LC) metalloprotease activity, and we identified a common pharmacophore for these molecules. In this study, we have focused on how the dynamic movement of amino acid residues in and surrounding the substrate binding cleft of the BoNT/A LC might affect inhibitor binding modes. The X-ray crystal structures of two BoNT/A LCs (PDB refcodes = 3BTA and 1E1H) were examined. Results from these analyses indicate that the core structural features of the examined BoNT/A LCs, including α-helices and β-sheets, remained relatively unchanged during 1 ns dynamics trajectories. However, conformational flexibility was observed in surface loops bordering the substrate binding clefts in both examined structures. Our analyses indicate that these loops may possess the ability to decrease the solvent accessibility of the substrate binding cleft, while at the same time creating new residue contacts for the inhibitors. Loop movements and conformational/positional analyses of residues within the substrate binding cleft are discussed with respect to BoNT/A LC inhibitor binding and our common pharmacophore for inhibition. The results from these studies may aid in the future identification/development of more potent small molecule inhibitors that take advantage of new binding contacts in the BoNT/A LC.

Original languageEnglish (US)
Pages (from-to)333-341
Number of pages9
JournalBioorganic and Medicinal Chemistry
Issue number2
StatePublished - Jan 17 2005


  • Bioterrorism
  • Botulinum neurotoxin
  • Drug discovery
  • Inhibitors
  • Metalloprotease
  • Molecular dynamics
  • Molecular modeling
  • Pharmacophore

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Fingerprint Dive into the research topics of 'Conformational sampling of the botulinum neurotoxin serotype a light chain: Implications for inhibitor binding'. Together they form a unique fingerprint.

Cite this