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[[Image:2pg7.gif|left|200px]]<br /><applet load="2pg7" size="350" color="white" frame="true" align="right" spinBox="true"
[[Image:2pg7.gif|left|200px]]
caption="2pg7, resolution 2.800&Aring;" />
 
'''Crystal Structure of Human Microsomal P450 2A6 N297Q/I300V'''<br />
{{Structure
|PDB= 2pg7 |SIZE=350|CAPTION= <scene name='initialview01'>2pg7</scene>, resolution 2.800&Aring;
|SITE=
|LIGAND= <scene name='pdbligand=HEM:PROTOPORPHYRIN IX CONTAINING FE'>HEM</scene>
|ACTIVITY= [http://en.wikipedia.org/wiki/Unspecific_monooxygenase Unspecific monooxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.14.1 1.14.14.1]
|GENE= CYP2A6 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
}}
 
'''Crystal Structure of Human Microsomal P450 2A6 N297Q/I300V'''
 


==Overview==
==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.
==Disease==
Known diseases associated with this structure: Coumarin resistance OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=122720 122720]], Lung cancer, resistance to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=122720 122720]], Nicotine addiction, protection from OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=122720 122720]]


==About this Structure==
==About this Structure==
2PG7 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=HEM:'>HEM</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Unspecific_monooxygenase Unspecific monooxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.14.1 1.14.14.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2PG7 OCA].  
2PG7 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2PG7 OCA].  


==Reference==
==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 Aug 15;464(2):197-206. Epub 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://www.ncbi.nlm.nih.gov/pubmed/17540336 17540336]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Single protein]]
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[[Category: heme]]
[[Category: heme]]
[[Category: indole]]
[[Category: indole]]
[[Category: monooxygenases]]
[[Category: monooxygenase]]
[[Category: mutant]]
[[Category: mutant]]
[[Category: p450]]
[[Category: p450]]
[[Category: p450 2a6]]
[[Category: p450 2a6]]


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