2v0m

From Proteopedia

Revision as of 08:49, 3 February 2008

CRYSTAL STRUCTURE OF HUMAN P450 3A4 IN COMPLEX WITH KETOCONAZOLE

Overview

Cytochrome P450 (CYP) 3A4 is the most promiscuous of the human CYP enzymes, and contributes to the metabolism of approximately 50% of marketed drugs., It is also the isoform most often involved in unwanted drug-drug, interactions. A better understanding of the molecular mechanisms governing, CYP3A4-ligand interaction therefore would be of great importance to any, drug discovery effort. Here, we present crystal structures of human CYP3A4, in complex with two well characterized drugs: ketoconazole and, erythromycin. In contrast to previous reports, the protein undergoes, dramatic conformational changes upon ligand binding with an increase in, the active site volume by >80%. The structures represent two distinct open, conformations of CYP3A4 because ketoconazole and erythromycin induce, different types of coordinate shifts. The binding of two molecules of, ketoconazole to the CYP3A4 active site and the clear indication of, multiple binding modes for erythromycin has implications for the, interpretation of the atypical kinetic data often displayed by CYP3A4. The, extreme flexibility revealed by the present structures also challenges any, attempt to apply computational design tools without the support of, relevant experimental data.

About this Structure

2V0M is a Single protein structure of sequence from Homo sapiens with and as ligands. This structure superseeds the now removed PDB entry 2J0C. Known structural/functional Site: . Full crystallographic information is available from OCA.

Reference

Structural basis for ligand promiscuity in cytochrome P450 3A4., Ekroos M, Sjogren T, Proc Natl Acad Sci U S A. 2006 Sep 12;103(37):13682-7. Epub 2006 Sep 5. PMID:16954191

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