title: 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.
authors.affiliation: Astex Technology, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Williams
authors.forename: Jose
authors.initials: J
authors.lastname: Cosme
authors.forename: Dijana Matak
authors.initials: DM
authors.lastname: Vinkovic
authors.forename: Alison
authors.initials: A
authors.lastname: Ward
authors.forename: Hayley C
authors.initials: HC
authors.lastname: Angove
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Day
authors.forename: Clemens
authors.initials: C
authors.lastname: Vonrhein
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Tickle
authors.forename: Harren
authors.initials: H
authors.lastname: Jhoti
mesh_terms: D001665:Binding Sites; D003460:Crystallization; D018360:Crystallography, X-Ray; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism*; D006418:Heme / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008797:Metyrapone / Q000378:metabolism*; D008958:Models, Molecular; D010649:Phenylalanine / Q000737:chemistry / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D014867:Water / Q000378:metabolism
chemical_list: D008024:Ligands; D014867:Water; D006418:Heme; D010649:Phenylalanine; D011374:Progesterone; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008797:Metyrapone