2v0m
From Proteopedia
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==Overview== | ==Overview== | ||
| - | Cytochrome P450 (CYP) 3A4 is the most promiscuous of the human CYP enzymes | + | 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== | ==About this Structure== | ||
| - | 2V0M is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=HEM:'>HEM</scene> and <scene name='pdbligand=KLN:'>KLN</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. This structure | + | 2V0M is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=HEM:'>HEM</scene> and <scene name='pdbligand=KLN:'>KLN</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. This structure supersedes the now removed PDB entry 2J0C. Known structural/functional Site: <scene name='pdbsite=AC1:Kln+Binding+Site+For+Chain+D'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2V0M OCA]. |
==Reference== | ==Reference== | ||
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[[Category: transmembrane]] | [[Category: transmembrane]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:52:13 2008'' |
Revision as of 16:52, 21 February 2008
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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 supersedes 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
Page seeded by OCA on Thu Feb 21 18:52:13 2008
Categories: Homo sapiens | Single protein | Ekroos, M. | Sjogren, T. | HEM | KLN | Cyp3a4 | Drug metabolizing enzyme | Endoplasmic reticulum | Heme | Iron | Ketoconazol | Membrane | Metal-binding | Microsome | Monooxygenase | Nadp | Oxidoreductase | P450 | Polymorphism | Transmembrane
