User:Yuan-Ping Pang/Sandbox 1
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Model: Botulinum Neurotoxin Serotype A Endopeptidase Liganded with a Nanomolar Small-Molecule Inhibitor HAB - by Yuan-Ping Pang
Botulinum neurotoxin serotype A (BoNTA) causes a life-threatening neuroparalytic disease known as botulism. Small-molecule inhibitors of BoNTA endopeptidase (BoNTAe) are sought in our laboratories as potential antidotes to antagonize the extracellular or intracellular BoNTA[1][2][3]. 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 is highly flexible or intrinsically disordered; the percentages of the top three most-populated conformations of the complex (Models 1-3) are 20.8%, 13.4% and 11.9%, respectively. To evaluate the computational methods, the coordinates of the three models are released before the forthcoming crystal structure of HAB•BoNTAe. Only 33% of the heavy atoms of HAB are released in the models below[4]. The full structure of HAB will be released upon manuscript acceptance[5].
Download the coordinates of Model 1 (PDB format)
Download the coordinates of Model 2 (PDB format)
Download the coordinates of Model 3 (PDB format)
References & Notes
- ↑ Serotype-selective, small-molecule inhibitors of the zinc endopeptidase of botulinum neurotoxin serotype A, Bioorg. Med. Chem., 14, 395-408 (2006)
- ↑ Computer-Aided Lead Optimization: Improved Small-Molecule Inhibitor of the Zinc Endopeptidase of Botulinum Neurotoxin Serotype A, PLoS ONE, 2(8): e761 (2007).
- ↑ Potent New Small-Molecule Inhibitor of Botulinum Neurotoxin Serotype A Endopeptidase Developed by Synthesis-Based Computer-Aided Molecular Design, PLoS ONE, 4(11): e7730 (2009).
- ↑ The models of HAB•BoNTAe were released at Mayo Research Protein Structure Prediction on March 5, 2010.
- ↑ 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.