DOI: 10.1126/science.1099736. Crystal Structures of Human Cytochrome P450 3A4 Bound to Metyrapone and Progesterone

Crystal Structures of Human Cytochrome P450 3A4 Bound to Metyrapone and Progesterone

10.1126/science.1099736

Crossref journal-article

American Association for the Advancement of Science (AAAS)

Science (221)

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.

Bibliography

Williams, P. A., Cosme, J., VinkovicÌ, 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, 305(5684), 683â686.

Authors 9

Pamela A. Williams (first)
Jose Cosme (additional)
Dijana Matak Vinković (additional)
Alison Ward (additional)
Hayley C. Angove (additional)
Philip J. Day (additional)
Clemens Vonrhein (additional)
Ian J. Tickle (additional)
Harren Jhoti (additional)

References 37 Referenced 698

10.1146/annurev.pharmtox.39.1.1
10.1124/dmd.30.4.355
10.1021/bi962359z
G. E. Schwab, J. L. Raucy, E. F. Johnson, Mol. Pharmacol.33, 493 (1988). / Mol. Pharmacol. (1988)
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10.1021/bi9715627
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K. E. Kenworthy, S. E. Clarke, J. Andrews, J. B. Houston, Drug Metab. Dispos.29, 1644 (2001). / Drug Metab. Dispos. (2001)
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J. C. Stevenset al., J. Pharmacol. Exp. Ther.290, 594 (1999). / J. Pharmacol. Exp. Ther. (1999)
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10.1073/pnas.96.5.1863
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10.1021/bi00399a022
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S. E. Graham-Lorence, J. A. Peterson, in Physiological Functions of Cytochrome P450 in Relation to Structure and Regulation, C. Jefcoate, Ed. (Jai Press, Greenwhich, CT, 1995), pp. 57–79. / Physiological Functions of Cytochrome P450 in Relation to Structure and Regulation (1995)
10.1023/A:1023813504011
We thank S. Rich S. Maman D. Cross S. Kirton and C. Murray for assistance with crystallization characterization and analysis; G. Williams for discussions; and F. W. Dahlquist for the provision of the pCWori+ expression vector. We acknowledge the European Synchrotron Radiation Facility for the provision of synchrotron radiation facilities and thank the industrial user group for assistance with data collection. Coordinates and structure factors of the ligand-free metyrapone- and progesterone-bound structures of CYP3A4 have been deposited in the Protein Data Bank (PDB) (entries 1W0E 1W0F and 1W0G).

Dates

Type	When
Created	21 years, 1 month ago (July 15, 2004, 8:31 p.m.)
Deposited	1 year, 7 months ago (Jan. 9, 2024, 8:52 p.m.)
Indexed	6 days, 11 hours ago (Aug. 30, 2025, 1:06 p.m.)
Issued	21 years, 1 month ago (July 30, 2004)
Published	21 years, 1 month ago (July 30, 2004)
Published Print	21 years, 1 month ago (July 30, 2004)

Funders 0

None

BibTeX

@article{Williams_2004, title={Crystal Structures of Human Cytochrome P450 3A4 Bound to Metyrapone and Progesterone}, volume={305}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.1099736}, DOI={10.1126/science.1099736}, number={5684}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Williams, Pamela A. and Cosme, Jose and Vinković, Dijana Matak and Ward, Alison and Angove, Hayley C. and Day, Philip J. and Vonrhein, Clemens and Tickle, Ian J. and Jhoti, Harren}, year={2004}, month=jul, pages={683–686} }

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