3K4F

X-Ray Crystal Structure of Human Heme Oxygenase-1 in Complex with 4-Phenyl-1-(1H-1,2,4-triazol-1-yl)-2-butanone

Summary for 3K4F

• Entry DOI: 10.2210/pdb3k4f/pdb
• Related: 1N45 3CZY 3HOK
• Descriptor: Heme oxygenase 1, PROTOPORPHYRIN IX CONTAINING FE, 4-phenyl-1-(1H-1,2,4-triazol-1-yl)butan-2-one, ... (6 entities in total)
• Functional Keywords: heme oxygenase-1 inhibitor complex, alpha helices, 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: 55889.18

Authors

Rahman, M.N.,Jia, Z. (deposition date: 2009-10-05, release date: 2009-12-15, Last modification date: 2023-09-06)

Primary citation

Roman, G.,Rahman, M.N.,Vukomanovic, D.,Jia, Z.,Nakatsu, K.,Szarek, W.A.
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.
Chem.Biol.Drug Des., 75:68-90, 2010

PubMed Abstract: A 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.

PubMed: 19954435
DOI: 10.1111/j.1747-0285.2009.00909.x

Experimental method

X-RAY DIFFRACTION (2.17 Å)