3t3q

Human Cytochrome P450 2A6 I208S/I300F/G301A/S369G in complex with Pilocarpine

spinqualitylabelsall models 3t3q, resolution 2.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3t3q is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 9PL, HEM Related: 3ebs, 2fdy, 1z11, 1z10, 2fdu, 2fdv, 2pg7, 2pg6, 2pg5, 2fdw, 3t3r, 3t3s, 3t3z Gene: CYP2A3, CYP2A6, CYP2A6 I208S/I300F/G301A/S369G (HUMAN) Activity: Unspecific monooxygenase, with EC number 1.14.14.1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [CP2A6_HUMAN] Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Constitutes the major nicotine C-oxidase. Acts as a 1,4-cineole 2-exo-monooxygenase. Possesses low phenacetin O-deethylation activity. Publication Abstract from PubMed Human xenobiotic-metabolizing cytochrome P450 (CYP) enzymes can each bind and monooxygenate a diverse set of substrates, including drugs, often producing a variety of metabolites. Additionally, a single ligand can interact with multiple CYP enzymes, but often the protein structural similarities and differences that mediate such overlapping selectivity are not well understood. Even though the CYP superfamily has a highly canonical global protein fold, there are large variations in the active site size, topology, and conformational flexibility. We have determined how a related set of three human CYP enzymes bind and interact with a common inhibitor, the muscarinic receptor agonist drug pilocarpine. Pilocarpine binds and inhibits the hepatic CYP2A6 and respiratory CYP2A13 enzymes much more efficiently than the hepatic CYP2E1 enzyme. To elucidate key residues involved in pilocarpine binding, crystal structures of CYP2A6 (2.4 A), CYP2A13 (3.0 A), CYP2E1 (2.35 A), and the CYP2A6 mutant enzyme, CYP2A6 I208S/I300F/G301A/S369G (2.1 A) have been determined with pilocarpine in the active site. In all four structures, pilocarpine coordinates to the heme iron, but comparisons reveal how individual residues lining the active sites of these three distinct human enzymes interact differently with the inhibitor pilocarpine. Database Structural data are available in the Protein Data Bank database under the accession numbers 3T3Q (CYP2A6 I208S/I300F/G301A/S369G with pilocarpine), 3T3R (CYP2A6 with pilocarpine), 3T3S (CYP2A13 with pilocarpine), and 3T3Z (CYP2E1 with pilocarpine). Structural comparison of cytochromes P450 2A6, 2A13, and 2E1 with pilocarpine.,Devore NM, Meneely KM, Bart AG, Stephens ES, Battaile KP, Scott EE FEBS J. 2011 Nov 3. doi: 10.1111/j.1742-4658.2011.08412.x. PMID:22051186 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cytochrome P450 3D structures

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