3hok

From Proteopedia

X-ray Crystal Structure of Human Heme Oxygenase-1 with (2R, 4S)-2-[2-(4-Chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4[((5-trifluoromethylpyridin-2-yl)thio)methyl]-1,3-dioxolane: A Novel, Inducible Binding Mode

PDB ID 3hok

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Structural highlights

3hok is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.19Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

HMOX1_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]

Function

HMOX1_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 PubMed

The crystal structure of human heme oxygenase-1 (HO-1) in complex with (2R,4S)-2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4[((5-tri fluoromethylpyridin-2-yl)thio)methyl]-1,3-dioxolane (4) reveals a novel, inducible binding mode. Inhibitor 4 coordinates the heme iron, with its chlorophenyl group bound in a distal hydrophobic pocket, as seen in previous structures. However, accommodation of the 5-trifluoromethylpyridin-2-yl group requires a significant shift in the proximal helix, inducing the formation of a hydrophobic pocket. This is the first example of an induced binding pocket observed in HO-1.

X-ray Crystal Structure of Human Heme Oxygenase-1 with (2R,4S)-2-[2-(4-Chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4[((5-tri fluoromethylpyridin-2-yl)thio)methyl]-1,3-dioxolane: A Novel, Inducible Binding Mode.,Rahman MN, Vlahakis JZ, Vukomanovic D, Szarek WA, Nakatsu K, Jia Z J Med Chem. 2009 Jul 14. PMID:19601578^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Yachie A, Niida Y, Wada T, Igarashi N, Kaneda H, Toma T, Ohta K, Kasahara Y, Koizumi S. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest. 1999 Jan;103(1):129-35. PMID:9884342 doi:10.1172/JCI4165
↑ Rahman MN, Vlahakis JZ, Vukomanovic D, Szarek WA, Nakatsu K, Jia Z. X-ray Crystal Structure of Human Heme Oxygenase-1 with (2R,4S)-2-[2-(4-Chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4[((5-tri fluoromethylpyridin-2-yl)thio)methyl]-1,3-dioxolane: A Novel, Inducible Binding Mode. J Med Chem. 2009 Jul 14. PMID:19601578 doi:10.1021/jm900434f