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PDBsum entry 3k4f

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protein ligands Protein-protein interface(s) links
Oxidoreductase PDB id
3k4f
Jmol
Contents
Protein chain
214 a.a. *
Ligands
HEM-Q86 ×2
HEZ ×2
SO4 ×2
Waters ×271
* Residue conservation analysis
PDB id:
3k4f
Name: Oxidoreductase
Title: X-ray crystal structure of human heme oxygenase-1 in complex with 4-phenyl-1-(1h-1,2,4-triazol-1-yl)-2-butanone
Structure: Heme oxygenase 1. Chain: a, b. Fragment: residues 1-233. Synonym: ho-1. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: hmox1, ho, ho1. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.17Å     R-factor:   0.225     R-free:   0.280
Authors: M.N.Rahman,Z.Jia
Key ref: G.Roman et al. (2010). 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. PubMed id: 19954435
Date:
05-Oct-09     Release date:   15-Dec-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P09601  (HMOX1_HUMAN) -  Heme oxygenase 1
Seq:
Struc:
288 a.a.
214 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.1.14.99.3  - Heme oxygenase (biliverdin-producing).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Protoheme + 3 AH2 + 3 O2 = biliverdin + Fe2+ + CO + 3 A + 3 H2O
Protoheme
Bound ligand (Het Group name = HEM)
matches with 95.00% similarity
+ 3 × AH(2)
+ 3 × O(2)
= biliverdin
+ Fe(2+)
+ CO
+ 3 × A
+ 3 × H(2)O
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     oxidation-reduction process   2 terms 
  Biochemical function     heme oxygenase (decyclizing) activity     1 term  

 

 
    reference    
 
 
Chem Biol Drug Des 75:68-90 (2010)
PubMed id: 19954435  
 
 
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.
G.Roman, M.N.Rahman, D.Vukomanovic, Z.Jia, K.Nakatsu, W.A.Szarek.
 
  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.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20555417 D.Vukomanovic, B.McLaughlin, M.N.Rahman, J.Z.Vlahakis, G.Roman, R.A.Dercho, R.T.Kinobe, M.Hum, J.F.Brien, Z.Jia, W.A.Szarek, and K.Nakatsu (2010).
Recombinant truncated and microsomal heme oxygenase-1 and -2: differential sensitivity to inhibitors.
  Can J Physiol Pharmacol, 88, 480-486.  
20652928 G.Roman, J.Z.Vlahakis, D.Vukomanovic, K.Nakatsu, and W.A.Szarek (2010).
Heme oxygenase inhibition by 1-aryl-2-(1h-imidazol-1-yl/1h-1,2,4-triazol-1-yl)ethanones and their derivatives.
  ChemMedChem, 5, 1541-1555.  
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