title: Comparative docking studies of CYP1b1 and its PCG-associated mutant forms.
abstract: Molecular docking has been used to compare and contrast the binding modes of oestradiol with the wild-type and some disease-associated mutant forms of the human CYP1b1 protein.The receptor structures used for docking were derived from molecular dynamics simulations of homology-modelled structures. Earlier studies involving molecular dynamics and principal component analysis indicated that mutations could have a disruptive effect on function,by destabilizing the native properties of the functionally important regions, especially those of the haem-binding and substrate-binding regions,which constitute the site of catalytic activity of the enzyme.In order to gain more insights into the possible differences in substrate-binding and catalysis between the wild-type and mutant proteins,molecular docking studies were carried out. Mutants showed altered protein -ligand interactions compared with the wild-type as a consequence of changes in the geometry of the substrate-binding region and in the position of haem relative to the active site. An important difference in ligand -protein interactions between the wild-type and mutants is the presence of stacking interaction with phenyl residues in the wild-type,which is either completely absent or considerably weaker in mutants.The present study revealed essential differences in the interactions between ligand and protein in wild-type and disease mutants,and helped in understanding the deleterious nature of disease mutations at the level of molecular function.
authors.affiliation: Centre for DNA Fingerprinting and Diagnostics (CDFD),ECIL Road, Nacharam, Hyderabad 500 076, India.
authors.forename: Malkaram Sridhar
authors.initials: MS
authors.lastname: Achary
authors.forename: Hampapathalu Adimurthy
authors.initials: HA
authors.lastname: Nagarajam
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004958:Estradiol / Q000737:chemistry / Q000378:metabolism; D005901:Glaucoma / Q000151:congenital* / Q000235:genetics*; D006801:Humans; D008956:Models, Chemical; D015394:Molecular Structure; D009154:Mutation; D011485:Protein Binding
chemical_list: D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1