3CZY

Crystal Structure of Human Heme Oxygenase-1 in Complex with 1-(Adamantan-1-yl)-2-(1H-imidazol-1-yl)ethanone

Summary for 3CZY

• Entry DOI: 10.2210/pdb3czy/pdb
• Descriptor: Heme oxygenase 1, PROTOPORPHYRIN IX CONTAINING FE, 1-(adamantan-1-yl)-2-(1H-imidazol-1-yl)ethanone, ... (4 entities in total)
• Functional Keywords: heme oxygenase-1 inhibitor complex, endoplasmic reticulum, heme, iron, metal-binding, microsome, oxidoreductase, phosphoprotein, polymorphism
• Biological source: Homo sapiens (human)
• Cellular location: Microsome: P09601
• Total number of polymer chains: 2
• Total formula weight: 55518.87

Authors

Jia, Z.,Rahman, M.N. (deposition date: 2008-04-30, release date: 2008-09-30, Last modification date: 2023-08-30)

Primary citation

Rahman, M.N.,Vlahakis, J.Z.,Szarek, W.A.,Nakatsu, K.,Jia, Z.
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.
J.Med.Chem., 51:5943-5952, 2008

PubMed 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.

PubMed: 18798608
DOI: 10.1021/jm800505m

Experimental method

X-RAY DIFFRACTION (1.54 Å)