3k4f | pdb_00003k4f
X-Ray Crystal Structure of Human Heme Oxygenase-1 in Complex with 4-Phenyl-1-(1H-1,2,4-triazol-1-yl)-2-butanone
Structural highlights
DiseaseHMOX1_HUMAN Defects in HMOX1 are the cause of heme oxygenase 1 deficiency (HMOX1D) [MIM:614034. A disease characterized by impaired stress hematopoiesis, resulting in marked erythrocyte fragmentation and intravascular hemolysis, coagulation abnormalities, endothelial damage, and iron deposition in renal and hepatic tissues. Clinical features include persistent hemolytic anemia, asplenia, nephritis, generalized erythematous rash, growth retardation and hepatomegaly.[1] FunctionHMOX1_HUMAN Heme oxygenase cleaves the heme ring at the alpha methene bridge to form biliverdin. Biliverdin is subsequently converted to bilirubin by biliverdin reductase. Under physiological conditions, the activity of heme oxygenase is highest in the spleen, where senescent erythrocytes are sequestrated and destroyed. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedA series of 1-azolyl-4-phenyl-2-butanones was designed and synthesized for the inhibition of heme oxygenases (heme oxygenase-1 and heme oxygenase-2). The replacement of imidazole by other azoles led to the discovery of novel 1H-1,2,4-triazole- and 1H-tetrazole-based inhibitors equipotent to a lead imidazole-based inhibitor. The inhibitors featuring 2H-tetrazole or 1H-1,2,3-triazole as the pharmacophore were less potent. Monosubstitution at position 2 or 4(5), or identical disubstitution at positions 4 and 5 of imidazole by a variety of electron-withdrawing or electron-donating, small or bulky groups, as well as the replacement of the traditional imidazole pharmacophore by an array of 3- or 5-substituted triazoles, identically 3,5-disubstituted triazoles, 5-substituted-1H- and 5-substituted-2H-tetrazoles proved to be detrimental to the inhibition of HO, with a few exceptions. The azole-dioxolanes and the azole-alcohols derived from the active azole-ketones were synthesized also, but these inhibitors were less active than the corresponding imidazole-based analogs. The first reported X-ray crystal structure of human heme oxygenase-1 in complex with a 1,2,4-triazole-based inhibitor, namely 4-phenyl-1-(1H-1,2,4-triazol-1-yl)-2-butanone, was also determined. The inhibitor binds to the human heme oxygenase-1 distal pocket through the coordination of heme iron by the N4 in the triazole moiety, whereas the phenyl group is stabilized by hydrophobic interactions from residues within the binding pocket. Heme oxygenase inhibition by 2-oxy-substituted 1-azolyl-4-phenylbutanes: effect of variation of the azole moiety. X-ray crystal structure of human heme oxygenase-1 in complex with 4-phenyl-1-(1H-1,2,4-triazol-1-yl)-2-butanone.,Roman G, Rahman MN, Vukomanovic D, Jia Z, Nakatsu K, Szarek WA Chem Biol Drug Des. 2010 Jan;75(1):68-90. PMID:19954435[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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