title: Homology model of 1alpha,25-dihydroxyvitamin D3 24-hydroxylase cytochrome P450 24A1 (CYP24A1): active site architecture and ligand binding.
abstract: Homology models of cytochrome P450 24A1 (CYP24A1) were constructed using three human P450 structures, CYP2C8, CYP2C9 and CYP3A4 as templates for the model building. Using molecular operating environment (MOE) software the lowest energy CYP24A1 model was then assessed for stereochemical quality and side chain environment. Further active site optimisation of the CYP24A1 model built using the CYP3A4 template was performed by molecular dynamics to generate a final CYP24A1 model. The natural substrate, 1,25-dihydroxyvitamin D(3) (calcitriol) and the CYP24 inhibitor (R)-N-(2-(1H-imidazol-1-yl)-2-phenylethyl)-4'-chlorobiphenyl-4-carboxamide ((R)-VID-400) were docked into the model allowing further validation of the active site architecture. Using the docking studies structurally and functionally important residues were identified with subsequent characterisation of secondary structure.
authors.affiliation: Medicinal Chemistry, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3XF, UK.
authors.forename: Mohamed Sayed
authors.initials: MS
authors.lastname: Gomaa
authors.forename: Claire
authors.initials: C
authors.lastname: Simons
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
mesh_terms: D000595:Amino Acid Sequence; D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry; D001665:Binding Sites; D002117:Calcitriol / Q000378:metabolism; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013250:Steroid Hydroxylases / Q000737:chemistry* / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D008024:Ligands; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol