title: Disease-causing mutations in proteins: structural analysis of the CYP1B1 mutations causing primary congenital glaucoma in humans.
abstract: In this communication, we report an in-depth structure-based analysis of the human CYP1b1 protein carrying disease-causing mutations that are discovered in patients suffering from primary congenital glaucoma (PCG). The "wild-type" and the PCG mutant structures of the human CYP1b1 protein obtained from comparative modeling were subjected to long molecular dynamics simulations with an intention of studying the possible impact of these mutations on the protein structure and hence its function. Analysis of time evolution as well as time averaged values of various structural properties--especially of those of the functionally important regions: the heme binding region, substrate binding region, and substrate access channel--gave some insights into the possible structural characteristics of the disease mutant and the wild-type forms of the protein. In a nutshell, compared to the wild-type the core regions in the mutant structures are associated with subtle but significant changes, and the functionally important regions seem to adopt such structures that are not conducive for the wild-type-like functionality.
authors.affiliation: Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India.
authors.forename: Malkaram S
authors.initials: MS
authors.lastname: Achary
authors.forename: Aramati B M
authors.initials: AB
authors.lastname: Reddy
authors.forename: Subhabrata
authors.initials: S
authors.lastname: Chakrabarti
authors.forename: Shirly G
authors.initials: SG
authors.lastname: Panicker
authors.forename: Anil K
authors.initials: AK
authors.lastname: Mandal
authors.forename: Niyaz
authors.initials: N
authors.lastname: Ahmed
authors.forename: Dorairajan
authors.initials: D
authors.lastname: Balasubramanian
authors.forename: Seyed E
authors.initials: SE
authors.lastname: Hasnain
authors.forename: Hampapathalu A
authors.initials: HA
authors.lastname: Nagarajaram
mesh_terms: D000595:Amino Acid Sequence; D001189:Aryl Hydrocarbon Hydroxylases; D001665:Binding Sites; D003198:Computer Simulation; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics*; D005901:Glaucoma / Q000151:congenital / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation
chemical_list: D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1