2pg6: Difference between revisions

Revision as of 19:29, 21 February 2008

Crystal Structure of Human Microsomal P450 2A6 L240C/N297Q

OverviewOverview

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.

About this StructureAbout this Structure

2PG6 is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Unspecific monooxygenase, with EC number 1.14.14.1 Full crystallographic information is available from OCA.

ReferenceReference

Structural insight into the altered substrate specificity of human cytochrome P450 2A6 mutants., Sansen S, Hsu MH, Stout CD, Johnson EF, Arch Biochem Biophys. 2007 Aug 15;464(2):197-206. Epub 2007 May 11. PMID:17540336

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 ==Overview==
-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.
+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.
 ==About this Structure==
@@ Line 10: / Line 10: @@
 ==Reference==
-Structural insight into the altered substrate specificity of human cytochrome P450 2A6 mutants., Sansen S, Hsu MH, Stout CD, Johnson EF, Arch Biochem Biophys. 2007 May 11;. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17540336 17540336]
+Structural insight into the altered substrate specificity of human cytochrome P450 2A6 mutants., Sansen S, Hsu MH, Stout CD, Johnson EF, Arch Biochem Biophys. 2007 Aug 15;464(2):197-206. Epub 2007 May 11. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17540336 17540336]
 [[Category: Homo sapiens]]
 [[Category: Single protein]]
 [[Category: Unspecific monooxygenase]]
-[[Category: Hsu, M.H.]]
+[[Category: Hsu, M H.]]
-[[Category: Johnson, E.F.]]
+[[Category: Johnson, E F.]]
 [[Category: Sansen, S.]]
-[[Category: Stout, C.D.]]
+[[Category: Stout, C D.]]
 [[Category: HEM]]
 [[Category: cyp2a6]]
@@ Line 28: / Line 28: @@
 [[Category: p450 2a6]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 13:37:19 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:29:05 2008''