Structures of Clostridium botulinum Neurotoxin Serotype A Light Chain Complexed with Small-Molecule Inhibitors Highlight Active-Site Flexibility
| Autor: | Kim D. Janda, Jack P. Kennedy, Saul Tzipori, Mark S. Hixon, Karen N. Allen, Nicholas R. Silvaggi, Grant E. Boldt |
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| Rok vydání: | 2007 |
| Předmět: |
Models
Molecular CHEMBIOL DNA Complementary Stereochemistry Bacterial Toxins Clinical Biochemistry Molecular Conformation Crystallography X-Ray medicine.disease_cause Immunoglobulin light chain 01 natural sciences Biochemistry 03 medical and health sciences Drug Discovery Hydrolase medicine Neurotoxin MICROBES Glycosides Cloning Molecular Binding site Molecular Biology 030304 developmental biology Pharmacology chemistry.chemical_classification 0303 health sciences Binding Sites Models Statistical biology 010405 organic chemistry Clostridium botulinum type A Active site General Medicine Small molecule Triterpenes 0104 chemical sciences Enzyme chemistry biology.protein Molecular Medicine Clostridium botulinum Antitoxins Chromatography Liquid |
| Zdroj: | Chemistry & Biology. 14:533-542 |
| ISSN: | 1074-5521 |
| Popis: | SummaryThe potential for the use of Clostridial neurotoxins as bioweapons makes the development of small-molecule inhibitors of these deadly toxins a top priority. Recently, screening of a random hydroxamate library identified a small-molecule inhibitor of C. botulinum Neurotoxin Serotype A Light Chain (BoNT/A-LC), 4-chlorocinnamic hydroxamate, a derivative of which has been shown to have in vivo efficacy in mice and no toxicity. We describe the X-ray crystal structures of BoNT/A-LC in complexes with two potent small-molecule inhibitors. The structures of the enzyme with 4-chlorocinnamic hydroxamate or 2,4-dichlorocinnamic hydroxamate bound are compared to the structure of the enzyme complexed with L-arginine hydroxamate, an inhibitor with modest affinity. Taken together, this suite of structures provides surprising insights into the BoNT/A-LC active site, including unexpected conformational flexibility at the S1′ site that changes the electrostatic environment of the binding pocket. Information gained from these structures will inform the design and optimization of more effective small-molecule inhibitors of BoNT/A-LC. |
| Databáze: | OpenAIRE |
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