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

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

¹Astex Technology, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK. ²Global Phasing Ltd., Sheraton House, Castle Park, Cambridge, CB3 0AX, UK.

*Present address: AstraZeneca, Research and Development, Charnwood, Bakewell Road, Loughborough, LE11 5RH, UK.

†To whom correspondence should be addressed. E-mail: [email protected]

Supporting Online Material: www.sciencemag.org/cgi/content/full/1099736/DC1; Materials and Methods; Figs. S1 to S3; Tables S1 to S3; References

29 April 2004; accepted 7 July 2004

Published online 15 July 2004; 10.1126/science.1099736

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Science 305(5684):p 683-686, July 30, 2004.

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.