title: X-ray crystal structure of human heme oxygenase-1 in complex with 1-(adamantan-1-yl)-2-(1H-imidazol-1-yl)ethanone: a common binding mode for imidazole-based heme oxygenase-1 inhibitors.
abstract: Development of inhibitors specific for heme oxygenases (HOs) should aid our understanding of the HO system and facilitate future therapeutic applications. The crystal structure of human HO-1 complexed with 1-(adamantan-1-yl)-2-(1H-imidazol-1-yl)ethanone (3) was determined. This inhibitor binds to the HO-1 distal pocket such that the imidazolyl moiety coordinates with heme iron while the adamantyl group is stabilized by a hydrophobic binding pocket. Distal helix flexibility, coupled with shifts in proximal residues and heme, acts to expand the distal pocket, thus accommodating the bulky inhibitor without displacing heme. Inhibitor binding effectively displaces the catalytically critical distal water ligand. Comparison with the binding of 2-[2-(4-chlorophenyl)ethyl]-2-[1H-imidazol-1-yl)methyl]-1,3-dioxolane (2) revealed a common binding mode, despite differing chemical structures beyond the imidazolyl moiety. The inhibitor binding pocket is flexible, yet contains well-defined subpockets to accommodate appropriate functional groups. On the basis of these structural insights, we rationalize binding features to optimize inhibitor design.
authors.affiliation: Department of Biochemistry, Queen's University, Kingston, Ontario, Canada
authors.forename: Mona N
authors.initials: MN
authors.lastname: Rahman
authors.forename: Jason Z
authors.initials: JZ
authors.lastname: Vlahakis
authors.forename: Walter A
authors.initials: WA
authors.lastname: Szarek
authors.forename: Kanji
authors.initials: K
authors.lastname: Nakatsu
authors.forename: Zongchao
authors.initials: Z
authors.lastname: Jia
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000737:chemistry* / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D055672:Static Electricity; D013329:Structure-Activity Relationship
chemical_list: C532572:1-(adamantan-1-yl)-2-(1H-imidazol-1-yl)ethanone; D004791:Enzyme Inhibitors; D007093:Imidazoles; C029899:imidazole; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D000218:Adamantane