title: Explicit water near the catalytic I helix Thr in the predicted solution structure of CYP2A4.
abstract: The solution structure of mouse cytochrome P450 2A4 (CYP2A4), a monooxygenase of deoxysteroids, was obtained using homology modeling and molecular dynamics. The solvent-equilibrated CYP2A4 preserves the essential features of CYP450s. A comparison of the models CYP2A4 and CYP2A4 with testosterone bound CYP2A4/T illustrates the changes induced by the binding of the substrate. Experimental evidence links four amino acid residues to the catalytic activity, substrate specificity, and regioselectivity of this enzyme. Three of the four amino acids are found within contact distance of the testosterone substrate, and therefore may control the binding of the substrate through direct interaction. Remarkably, a water complex previously observed in x-ray crystal structure forms near the bulge in the central I helix that contains a conserved Thr. The properties of the I helix are computed in the context of the presence or absence of ligand.
authors.affiliation: Department of Chemistry, University of North Carolina, Chapel Hill, 27599, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Gorokhov
authors.forename: Masahiko
authors.initials: M
authors.lastname: Negishi
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
authors.forename: Lars C
authors.initials: LC
authors.lastname: Pedersen
authors.forename: Lalith
authors.initials: L
authors.lastname: Perera
authors.forename: Tom A
authors.initials: TA
authors.lastname: Darden
authors.forename: Lee G
authors.initials: LG
authors.lastname: Pedersen
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry*; D003198:Computer Simulation; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D000072467:Cytochrome P450 Family 2; D004789:Enzyme Activation; D004795:Enzyme Stability; D006801:Humans; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D012996:Solutions / Q000737:chemistry; D013255:Steroid 21-Hydroxylase / Q000737:chemistry; D013250:Steroid Hydroxylases / Q000737:chemistry*; D013379:Substrate Specificity; D013739:Testosterone / Q000737:chemistry*; D013912:Threonine / Q000737:chemistry*; D014867:Water / Q000737:chemistry*
chemical_list: D000596:Amino Acids; D012996:Solutions; D014867:Water; D013912:Threonine; D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C065407:CYP2C5 protein, Oryctolagus cuniculus; C460223:Cyp2a4 protein, mouse; D000072467:Cytochrome P450 Family 2; D013255:Steroid 21-Hydroxylase