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PDBsum entry 2pg5

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protein ligands Protein-protein interface(s) links
Oxidoreductase PDB id
2pg5
Jmol
Contents
Protein chain
464 a.a. *
Ligands
HEM ×4
EDO ×4
Waters ×648
* Residue conservation analysis
PDB id:
2pg5
Name: Oxidoreductase
Title: Crystal structure of human microsomal p450 2a6 n297q
Structure: Cytochrome p450 2a6. Chain: a, b, c, d. Synonym: cypiia6, coumarin 7-hydroxylase, p450 iia3, cyp2a3, p450i. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: cyp2a6. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.95Å     R-factor:   0.215     R-free:   0.239
Authors: S.Sansen,M.H.Hsu,C.D.Stout,E.F.Johnson
Key ref: S.Sansen et al. (2007). Structural insight into the altered substrate specificity of human cytochrome P450 2A6 mutants. Arch Biochem Biophys, 464, 197-206. PubMed id: 17540336
Date:
06-Apr-07     Release date:   24-Jul-07    
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q16696  (CP2AD_HUMAN) -  Cytochrome P450 2A13
Seq:
Struc:
494 a.a.
464 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 28 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.1.14.14.1  - Unspecific monooxygenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: RH + reduced flavoprotein + O2 = ROH + oxidized flavoprotein + H2O
RH
+ reduced flavoprotein
+ O(2)
= ROH
+ oxidized flavoprotein
+ H(2)O
      Cofactor: Heme-thiolate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   5 terms 
  Biological process     small molecule metabolic process   3 terms 
  Biochemical function     oxidoreductase activity     8 terms  

 

 
    Added reference    
 
 
Arch Biochem Biophys 464:197-206 (2007)
PubMed id: 17540336  
 
 
Structural insight into the altered substrate specificity of human cytochrome P450 2A6 mutants.
S.Sansen, M.H.Hsu, C.D.Stout, E.F.Johnson.
 
  ABSTRACT  
 
Human P450 2A6 displays a small active site that is well adapted for the oxidation of small planar substrates. Mutagenesis of CYP2A6 resulted in an increased catalytic efficiency for indole biotransformation to pigments and conferred a capacity to oxidize substituted indoles (Wu, Z.-L., Podust, L.M., Guengerich, F.P. J. Biol. Chem. 49 (2005) 41090-41100.). Here, we describe the structural basis that underlies the altered metabolic profile of three mutant enzymes, P450 2A6 N297Q, L240C/N297Q and N297Q/I300V. The Asn297 substitution abolishes a potential hydrogen bonding interaction with substrates in the active site, and replaces a structural water molecule between the helix B'-C region and helix I while maintaining structural hydrogen bonding interactions. The structures of the P450 2A6 N297Q/L240C and N297Q/I300V mutants provide clues as to how the protein can adapt to fit the larger substituted indoles in the active site, and enable a comparison with other P450 family 2 enzymes for which the residue at the equivalent position was seen to function in isozyme specificity, structural integrity and protein flexibility.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19129847 D.Ghosh, J.Griswold, M.Erman, and W.Pangborn (2009).
Structural basis for androgen specificity and oestrogen synthesis in human aromatase.
  Nature, 457, 219-223.
PDB code: 3eqm
19074523 K.E.Schlicht, J.Z.Berg, and S.E.Murphy (2009).
Effect of CYP2A13 active site mutation N297A on metabolism of coumarin and tobacco-specific nitrosamines.
  Drug Metab Dispos, 37, 665-671.  
19104915 M.K.Leong, Y.M.Chen, H.B.Chen, and P.H.Chen (2009).
Development of a New Predictive Model for Interactions with Human Cytochrome P450 2A6 Using Pharmacophore Ensemble/Support Vector Machine (PhE/SVM) Approach.
  Pharm Res, 26, 987.  
18622259 D.Choudhary, I.Jansson, M.Sarfarazi, and J.B.Schenkman (2008).
Characterization of the biochemical and structural phenotypes of four CYP1B1 mutations observed in individuals with primary congenital glaucoma.
  Pharmacogenet Genomics, 18, 665-676.  
18622598 E.M.Isin, and F.P.Guengerich (2008).
Substrate binding to cytochromes P450.
  Anal Bioanal Chem, 392, 1019-1030.  
18484912 E.Stjernschantz, N.P.Vermeulen, and C.Oostenbrink (2008).
Computational prediction of drug binding and rationalisation of selectivity towards cytochromes P450.
  Expert Opin Drug Metab Toxicol, 4, 513-527.  
18779312 N.M.DeVore, B.D.Smith, M.J.Urban, and E.E.Scott (2008).
Key residues controlling phenacetin metabolism by human cytochrome P450 2A enzymes.
  Drug Metab Dispos, 36, 2582-2590.
PDB code: 3ebs
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.