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PDBsum entry 3czy

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protein ligands Protein-protein interface(s) links
Oxidoreductase PDB id
3czy
Jmol
Contents
Protein chain
214 a.a. *
Ligands
HEM-AD8 ×2
Waters ×503
* Residue conservation analysis
PDB id:
3czy
Name: Oxidoreductase
Title: Crystal structure of human heme oxygenase-1 in complex with 1-(adamantan-1-yl)-2-(1h-imidazol-1-yl)ethanone
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.
Resolution:
1.54Å     R-factor:   0.195     R-free:   0.226
Authors: Z.Jia,M.N.Rahman
Key ref: M.N.Rahman et al. (2008). X-ray crystal structure of human heme oxygenase-1 in complex with 1-(adamantan-1-yl)-2-(1H-imidazol-1-yl)ethanone: a common binding mode for imidazole-based heme oxygenase-1 inhibitors. J Med Chem, 51, 5943-5952. PubMed id: 18798608 DOI: 10.1021/jm800505m
Date:
30-Apr-08     Release date:   30-Sep-08    
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    
 
 
DOI no: 10.1021/jm800505m J Med Chem 51:5943-5952 (2008)
PubMed id: 18798608  
 
 
X-ray crystal structure of human heme oxygenase-1 in complex with 1-(adamantan-1-yl)-2-(1H-imidazol-1-yl)ethanone: a common binding mode for imidazole-based heme oxygenase-1 inhibitors.
M.N.Rahman, J.Z.Vlahakis, W.A.Szarek, K.Nakatsu, Z.Jia.
 
  ABSTRACT  
 
Development of inhibitors specific for heme oxygenases (HOs) should aid our understanding of the HO system and facilitate future therapeutic applications. The crystal structure of human HO-1 complexed with 1-(adamantan-1-yl)-2-(1H-imidazol-1-yl)ethanone (3) was determined. This inhibitor binds to the HO-1 distal pocket such that the imidazolyl moiety coordinates with heme iron while the adamantyl group is stabilized by a hydrophobic binding pocket. Distal helix flexibility, coupled with shifts in proximal residues and heme, acts to expand the distal pocket, thus accommodating the bulky inhibitor without displacing heme. Inhibitor binding effectively displaces the catalytically critical distal water ligand. Comparison with the binding of 2-[2-(4-chlorophenyl)ethyl]-2-[1H-imidazol-1-yl)methyl]-1,3-dioxolane (2) revealed a common binding mode, despite differing chemical structures beyond the imidazolyl moiety. The inhibitor binding pocket is flexible, yet contains well-defined subpockets to accommodate appropriate functional groups. On the basis of these structural insights, we rationalize binding features to optimize inhibitor design.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21354674 J.Liu, D.Obando, V.Liao, T.Lifa, and R.Codd (2011).
The many faces of the adamantyl group in drug design.
  Eur J Med Chem, 46, 1949-1963.  
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
20014790 J.D.Martell, H.Li, T.Doukov, P.Martásek, L.J.Roman, M.Soltis, T.L.Poulos, and R.B.Silverman (2010).
Heme-coordinating inhibitors of neuronal nitric oxide synthase. Iron-thioether coordination is stabilized by hydrophobic contacts without increased inhibitor potency.
  J Am Chem Soc, 132, 798-806.
PDB codes: 3jt3 3jt4 3jt5 3jt6 3jt7 3jt8 3jt9 3jta
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.  
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.