3TGM

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

Summary for 3TGM

• Entry DOI: 10.2210/pdb3tgm/pdb
• Related: 1N45 3CZY 3HOK 3K4F
• Descriptor: Heme oxygenase 1, PROTOPORPHYRIN IX CONTAINING FE, 1-(1H-imidazol-1-yl)-4,4-diphenylbutan-2-one, ... (5 entities in total)
• Functional Keywords: alpha helix, oxidoreductase, heme, microsomes, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Microsome: P09601
• Total number of polymer chains: 2
• Total formula weight: 55729.10

Authors

Rahman, M.N.,Jia, Z. (deposition date: 2011-08-17, release date: 2012-02-01, Last modification date: 2023-09-13)

Primary citation

Rahman, M.N.,Vlahakis, J.Z.,Vukomanovic, D.,Lee, W.,Szarek, W.A.,Nakatsu, K.,Jia, Z.
A novel, "double-clamp" binding mode for human heme oxygenase-1 inhibition.
Plos One, 7:e29514-e29514, 2012

PubMed Abstract: The development of heme oxygenase (HO) inhibitors is critical in dissecting and understanding the HO system and for potential therapeutic applications. We have established a program to design and optimize HO inhibitors using structure-activity relationships in conjunction with X-ray crystallographic analyses. One of our previous complex crystal structures revealed a putative secondary hydrophobic binding pocket which could be exploited for a new design strategy by introducing a functional group that would fit into this potential site. To test this hypothesis and gain further insights into the structural basis of inhibitor binding, we have synthesized and characterized 1-(1H-imidazol-1-yl)-4,4-diphenyl-2-butanone (QC-308). Using a carbon monoxide (CO) formation assay on rat spleen microsomes, the compound was found to be ∼15 times more potent (IC(50) = 0.27±0.07 µM) than its monophenyl analogue, which is already a potent compound in its own right (QC-65; IC(50) = 4.0±1.8 µM). The crystal structure of hHO-1 with QC-308 revealed that the second phenyl group in the western region of the compound is indeed accommodated by a definitive secondary proximal hydrophobic pocket. Thus, the two phenyl moieties are each stabilized by distinct hydrophobic pockets. This "double-clamp" binding offers additional inhibitor stabilization and provides a new route for improvement of human heme oxygenase inhibitors.

PubMed: 22276118
DOI: 10.1371/journal.pone.0029514

Experimental method

X-RAY DIFFRACTION (2.85 Å)