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Published Online July 15, 2004
Science DOI: 10.1126/science.1099736

Reports

Submitted on April 29, 2004
Accepted on July 7, 2004

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

Pamela A. Williams 1, Jose Cosme 1, Dijana Matak Vinkovic 1, Alison Ward 1{dagger}, Hayley C. Angove 1, Philip J. Day 1, Clemens Vonrhein 2, Ian J. Tickle 1, Harren Jhoti 1*

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

* To whom correspondence should be addressed.
Harren Jhoti , E-mail: h.jhoti{at}astex-technology.com

{dagger}Present address: AstraZeneca, R&D Charnwood, Bakewell Road, Loughborough, LE11 5RH, UK.

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 over 90% of marketed drugs. Cytochrome P450 3A4 (CYP3A4) metabolizes more drug molecules than all other isoforms combined. Here we report the first crystal structures of CYP3A4, un-liganded, bound to the inhibitor metyrapone and to the substrate progesterone. The structures reveal 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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