Crystal Structures of Human Cytochrome P450 3A4 Bound to Metyrapone and Progesterone
Pamela A. Williams,1
Jose Cosme,1
Dijana Matak Vinkovi
,1
Alison Ward,1*
Hayley C. Angove,1
Philip J. Day,1
Clemens Vonrhein,2
Ian J. Tickle,1
Harren Jhoti1
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.
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.
* Present address: AstraZeneca, Research and Development, Charnwood, Bakewell Road, Loughborough, LE11 5RH, UK.
To whom correspondence should be addressed. E-mail: h.jhoti{at}astex-technology.com
