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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Madrona, Yarrow De Montellano, Paul R. Ortiz Lampe, Jed N. Nishida, Clinton R. Basudhar, Debashree Kandel, Sylvie |
| Description | Author Affiliation: Basudhar D ( From the Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, California 94158.); Madrona Y ( From the Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, California 94158.); Kandel S ( XenoTech, LLC, Lenexa, Kansas 66219, and.); Lampe JN ( the Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160.); Nishida CR ( From the Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, California 94158.); de Montellano PR ( From the Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, California 94158, Ortiz@cgl.ucsf.edu.) |
| Abstract | Defining the conformational states of cytochrome P450 active sites is critical for the design of agents that minimize drug-drug interactions, the development of isoform-specific P450 inhibitors, and the engineering of novel oxidative catalysts. We used two-dimensional (1)H,(15)N HSQC chemical shift perturbation mapping of (15)N-labeled Phe residues and x-ray crystallography to examine the ligand-dependent conformational dynamics of CYP119. Active site Phe residues were most affected by the binding of azole inhibitors and fatty acid substrates, in agreement with active site localization of the conformational changes. This was supported by crystallography, which revealed movement of the F-G loop with various azoles. Nevertheless, the NMR chemical shift perturbations caused by azoles and substrates were distinguishable. The absence of significant chemical shift perturbations with several azoles revealed binding of ligands to an open conformation similar to that of the ligand-free state. In contrast, 4-phenylimidazole caused pronounced NMR changes involving Phe-87, Phe-144, and Phe-153 that support the closed conformation found in the crystal structure. The same closed conformation is observed by NMR and crystallography with a para-fluoro substituent on the 4-phenylimidazole, but a para-chloro or bromo substituent engendered a second closed conformation. An open conformation is thus favored in solution with many azole ligands, but para-substituted phenylimidazoles give rise to two closed conformations that depend on the size of the para-substituent. The results suggest that ligands selectively stabilize discrete cytochrome P450 conformational states. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 16 |
| Volume Number | 290 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2015-04-17 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Archaeal Proteins Chemistry Cytochrome P-450 Enzyme System Models, Molecular Sulfolobus Acidocaldarius Amino Acid Motifs Antagonists & Inhibitors Genetics Metabolism Catalytic Domain Crystallography, X-Ray Enzyme Inhibitors Fatty Acids Gene Expression Imidazoles Ligands Molecular Sequence Data Nuclear Magnetic Resonance, Biomolecular Peptide Mapping Protein Stability Protein Structure, Secondary Protein Structure, Tertiary Recombinant Proteins Enzymology Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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