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PDBsum entry 2pg7
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Oxidoreductase
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PDB id
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2pg7
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Contents |
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* Residue conservation analysis
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PDB id:
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| Name: |
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Oxidoreductase
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Title:
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Crystal structure of human microsomal p450 2a6 n297q/i300v
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Structure:
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Cytochrome p450 2a6. Chain: a, b, c, d. Synonym: cypiia6, coumarin 7-hydroxylase, p450 iia3, cyp2a3, p450i. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: cyp2a6. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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2.80Å
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R-factor:
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0.235
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R-free:
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0.289
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Authors:
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S.Sansen,M.H.Hsu,C.D.Stout,E.F.Johnson
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Key ref:
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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:
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Date:
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06-Apr-07
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Release date:
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24-Jul-07
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PROCHECK
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Headers
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References
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Q16696
(CP2AD_HUMAN) -
Cytochrome P450 2A13 from Homo sapiens
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Seq:
Struc:
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494 a.a.
464 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 28 residue positions (black
crosses)
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Enzyme class:
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E.C.1.14.14.1
- unspecific monooxygenase.
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Reaction:
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an organic molecule + reduced [NADPH--hemoprotein reductase] + O2 = an alcohol + oxidized [NADPH--hemoprotein reductase] + H2O + H+
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organic molecule
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+
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reduced [NADPH--hemoprotein reductase]
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+
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O2
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=
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alcohol
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+
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oxidized [NADPH--hemoprotein reductase]
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+
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H2O
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+
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H(+)
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Cofactor:
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Heme-thiolate
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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Arch Biochem Biophys
464:197-206
(2007)
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PubMed id:
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Structural insight into the altered substrate specificity of human cytochrome P450 2A6 mutants.
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S.Sansen,
M.H.Hsu,
C.D.Stout,
E.F.Johnson.
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ABSTRACT
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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.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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D.Ghosh,
J.Griswold,
M.Erman,
and
W.Pangborn
(2009).
Structural basis for androgen specificity and oestrogen synthesis in human aromatase.
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Nature,
457,
219-223.
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PDB code:
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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.
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Drug Metab Dispos,
37,
665-671.
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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.
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Pharm Res,
26,
987.
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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.
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Pharmacogenet Genomics,
18,
665-676.
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E.M.Isin,
and
F.P.Guengerich
(2008).
Substrate binding to cytochromes P450.
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Anal Bioanal Chem,
392,
1019-1030.
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E.Stjernschantz,
N.P.Vermeulen,
and
C.Oostenbrink
(2008).
Computational prediction of drug binding and rationalisation of selectivity towards cytochromes P450.
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Expert Opin Drug Metab Toxicol,
4,
513-527.
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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.
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Drug Metab Dispos,
36,
2582-2590.
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PDB code:
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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.
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Links
