The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.
Crystal Structures of Human Cytochrome P450 3A4 Bound to Metyrapone and Progesterone
Abstract
Cytochromes P450 (P450s) metabolize a wide range of endogenous compounds and xenobiotics, such as pollutants, environmental compounds, and drug molecules. The microsomal, membrane-associated, P450 isoforms CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP2E1, and CYP1A2 are responsible for the oxidative metabolism of more than 90% of marketed drugs. Cytochrome P450 3A4 (CYP3A4) metabolizes more drug molecules than all other isoforms combined. Here we report three crystal structures of CYP3A4: unliganded, bound to the inhibitor metyrapone, and bound to the substrate progesterone. The structures revealed a surprisingly small active site, with little conformational change associated with the binding of either compound. An unexpected peripheral binding site is identified, located above a phenylalanine cluster, which may be involved in the initial recognition of substrates or allosteric effectors.
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Cites
Structure of a cytochrome P450-redox partner electron-transfer complex
Sevrioukova, I. F., Li, H., Zhang, H., Peterson, J. A., & Poulos, T. L. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.5.1863 · Cited by 501
Cited by
Structure and chemistry of cytochrome p450
Denisov, I. G., Makris, T. M., Sligar, S. G., & Schlichting, I. (2005) · Chemical Reviews · doi:10.1021/cr0307143 · Cited by 2,106
Structural basis for androgen specificity and oestrogen synthesis in human aromatase
Ghosh, D., Griswold, J., Erman, M., & Pangborn, W. (2009) · Nature · doi:10.1038/nature07614 · Cited by 618
Can we rationally design promiscuous drugs?
HOPKINS, A., MASON, J., & OVERINGTON, J. (2006) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2006.01.013 · Cited by 469
Searching for new allosteric sites in enzymes
Hardy, J. A., & Wells, J. A. (2004) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2004.10.009 · Cited by 329
Kroiss, M., Quinkler, M., Lutz, W. K., Allolio, B., & Fassnacht, M. (2011) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2011.04214.x · Cited by 148
Metadata
- Authors
- Williams, P. A., Cosme, J., Vinković, D. M., Ward, A., Angove, H. C., Day, P. J., Vonrhein, C., Tickle, I. J., & Jhoti, H.
- Venue
- Science
- Published
- 2004-07-30
- Volume
- 305
- Issue
- 5684
- Pages
- 683-686
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2156423252
- Cited by
- 806
- References
- 1
- FWCI
- 48.88
- Type
- journal article
- Language
- en
- Open access
- closed
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- Williams, P. A., Cosme, J., Vinković, D. M., Ward, A., Angove, H. C., Day, P. J., Vonrhein, C., Tickle, I. J., & Jhoti, H. (2004). Crystal Structures of Human Cytochrome P450 3A4 Bound to Metyrapone and Progesterone. Science. https://doi.org/10.1126/science.1099736
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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