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PDBsum entry 2dy5

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protein ligands metals links
Oxidoreductase PDB id
2dy5
Jmol
Contents
Protein chain
214 a.a. *
Ligands
HEM-224
Metals
_CL
Waters ×10
* Residue conservation analysis
PDB id:
2dy5
Name: Oxidoreductase
Title: Crystal structure of rat heme oxygenase-1 in complex with heme and 2-[2-(4-chlorophenyl)ethyl]-2-[(1h-imidazol-1-yl) methyl]-1,3-dioxolane
Structure: Heme oxygenase 1. Chain: a. Fragment: c-terminal truncated form. Synonym: ho-1, hsp32. Engineered: yes
Source: Rattus norvegicus. Norway rat. Organism_taxid: 10116. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.70Å     R-factor:   0.194     R-free:   0.248
Authors: M.Sugishima,H.Takahashi,K.Fukuyama
Key ref: M.Sugishima et al. (2007). X-ray crystallographic and biochemical characterization of the inhibitory action of an imidazole-dioxolane compound on heme oxygenase. Biochemistry, 46, 1860-1867. PubMed id: 17253780 DOI: 10.1021/bi062264p
Date:
06-Sep-06     Release date:   22-May-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P06762  (HMOX1_RAT) -  Heme oxygenase 1
Seq:
Struc:
289 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!
  Cellular component     membrane   9 terms 
  Biological process     intracellular signal transduction   39 terms 
  Biochemical function     signal transducer activity     9 terms  

 

 
    reference    
 
 
DOI no: 10.1021/bi062264p Biochemistry 46:1860-1867 (2007)
PubMed id: 17253780  
 
 
X-ray crystallographic and biochemical characterization of the inhibitory action of an imidazole-dioxolane compound on heme oxygenase.
M.Sugishima, Y.Higashimoto, T.Oishi, H.Takahashi, H.Sakamoto, M.Noguchi, K.Fukuyama.
 
  ABSTRACT  
 
Heme oxygenase (HO) catalyzes the regiospecific cleavage of the porphyrin ring of heme using reducing equivalents and O2 to produce biliverdin, iron, and CO. Because CO has a cytoprotective effect through the p38-MAPK pathway, HO is a potential therapeutic target in cancer. In fact, inhibition of the HO isoform HO-1 reduces Kaposi sarcoma tumor growth. Imidazole-dioxolane compounds have recently attracted attention because they have been reported to specifically inhibit HO-1, but not HO-2, unlike Cr-containing protoporphyrin IX, a classical inhibitor of HO, that inhibits not only both HO isoforms but also other hemoproteins. The inhibitory mechanism of imidazole-dioxolane compounds, however, has not yet been characterized. Here, we determine the crystal structure of the ternary complex of rat HO-1, heme, and an imidazole-dioxolane compound, 2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-1,3-dioxolane. This compound bound on the distal side of the heme iron, where the imidazole and 4-chlorophenyl groups were bound to the heme iron and the hydrophobic cavity in HO, respectively. Binding of the bulky inhibitor in the narrow distal pocket shifted the distal helix to open the distal site and moved both the heme and the proximal helix. Furthermore, the biochemical characterization revealed that the catalytic reactions of both HO-1 and HO-2 were completely stopped after the formation of verdoheme in the presence of the imidazole-dioxolane compound. This result should be mainly due to the lower reactivity of the inhibitor-bound verdoheme with O2 compared to the reactivity of the inhibitor-bound heme with O2.
 

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.  
19954435 G.Roman, M.N.Rahman, D.Vukomanovic, Z.Jia, K.Nakatsu, and W.A.Szarek (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.
PDB code: 3k4f
19694439 J.P.Evans, S.Kandel, and P.R.Ortiz de Montellano (2009).
Isocyanides inhibit human heme oxygenases at the verdoheme stage.
  Biochemistry, 48, 8920-8928.  
18841169 T.Morisawa, R.J.Wong, V.K.Bhutani, H.J.Vreman, and D.K.Stevenson (2008).
Inhibition of heme oxygenase activity in newborn mice by azalanstat.
  Can J Physiol Pharmacol, 86, 651-659.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.