User:Yuan-Ping Pang/HAB•BoNTAe

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Theoretical Model: The protein structure described on this page was determined theoretically, and hence should be interpreted with caution.

Model: Botulinum Neurotoxin Serotype A Endopeptidase Liganded with a Small-Molecule Inhibitor HAB

Botulinum neurotoxin serotype A (BoNTA) causes botulism[1][2][3]. Small-molecule inhibitors of BoNTA endopeptidase (BoNTAe) are sought in our laboratories as potential antidotes to antagonize the extracellular or intracellular BoNTA[4][5][6]. HAB is one such inhibitor that exhibits nanomolar potency in inhibiting BoNTAe (to be published). Multiple molecular dynamics simulations of HAB•BoNTAe (20 10-ns-long simulations) suggest that one functional group of HAB is highly flexible or intrinsically disordered; the percentages of the top three most-populated conformations of the complex (Models 1-3) are 21%, 13% and 12%, respectively. To evaluate the computational methods used for generating HAB•BoNTAe, the coordinates of the three models were released before the forthcoming crystal structure of HAB•BoNTAe. Only 33% of the heavy atoms of HAB are provided in the released models[7]. The full structure of HAB will be released upon manuscript acceptance[8].

Download the coordinates of Models 1 (Hab1.pdb), 2 (Hab2.pdb), and 3 (Hab3.pdb) (PDB format)

References & Notes

  1. Botulism in the United States - a clinical and epidemiologic review, Ann Intern Med 129:221-228 1998
  2. Botulinum toxin as a biological weapon: medical and public health management, JAMA 285:1059-1070 2001
  3. U.S. Army Botulinum Neurotoxin (BoNT) medical therapeutics research program: Past accomplishments and future directions, Drug Dev Res 70:266-278 2009
  4. Serotype-selective, small-molecule inhibitors of the zinc endopeptidase of botulinum neurotoxin serotype A, Bioorg Med Chem 14:395-408 2006
  5. Computer-aided lead optimization: improved small-molecule inhibitor of the zinc endopeptidase of botulinum neurotoxin serotype A, PLoS ONE 2:e761 2007
  6. Potent new small-molecule inhibitor of botulinum neurotoxin serotype A endopeptidase developed by synthesis-based computer-aided molecular design, PLoS ONE 4:e7730 2009
  7. The models of HAB•BoNTAe were released at Mayo Research Protein Structure Prediction on March 5, 2010.
  8. This author thanks Professor Joel L. Sussman and his colleagues for their creation and maintenance of PROTEOPEDIA that permits archiving computational models of macromolecular structures and assessment of protein structure prediction made prior to experimental structures.

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Yuan-Ping Pang

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