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==Crystal Structure Of Human Microsomal P450 2A6 with the inhibitor (5-(Pyridin-3-yl)furan-2-yl)methanamine bound== | ==Crystal Structure Of Human Microsomal P450 2A6 with the inhibitor (5-(Pyridin-3-yl)furan-2-yl)methanamine bound== | ||
<StructureSection load='2fdw' size='340' side='right' caption='[[2fdw]], [[Resolution|resolution]] 2.05Å' scene=''> | <StructureSection load='2fdw' size='340' side='right'caption='[[2fdw]], [[Resolution|resolution]] 2.05Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2fdw]] is a 4 chain structure with sequence from [ | <table><tr><td colspan='2'>[[2fdw]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2FDW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2FDW FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=D3G:(5-(PYRIDIN-3-YL)FURAN-2-YL)METHANAMINE'>D3G</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=D3G:(5-(PYRIDIN-3-YL)FURAN-2-YL)METHANAMINE'>D3G</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1z10|1z10]], [[1z11|1z11]], [[2fdu|2fdu]], [[2fdv|2fdv]], [[2fdy|2fdy]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1z10|1z10]], [[1z11|1z11]], [[2fdu|2fdu]], [[2fdv|2fdv]], [[2fdy|2fdy]]</div></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP2A6 ([ | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP2A6 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Unspecific_monooxygenase Unspecific monooxygenase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.14.1 1.14.14.1] </span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2fdw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2fdw OCA], [https://pdbe.org/2fdw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2fdw RCSB], [https://www.ebi.ac.uk/pdbsum/2fdw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2fdw ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[[ | [[https://www.uniprot.org/uniprot/CP2A6_HUMAN CP2A6_HUMAN]] Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Constitutes the major nicotine C-oxidase. Acts as a 1,4-cineole 2-exo-monooxygenase. Possesses low phenacetin O-deethylation activity.<ref>PMID:1889415</ref> <ref>PMID:1944238</ref> <ref>PMID:11695850</ref> <ref>PMID:16086027</ref> <ref>PMID:17125252</ref> <ref>PMID:18779312</ref> | ||
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
[[Image:Consurf_key_small.gif|200px|right]] | [[Image:Consurf_key_small.gif|200px|right]] | ||
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==See Also== | ==See Also== | ||
*[[Cytochrome P450|Cytochrome P450]] | *[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Human]] | [[Category: Human]] | ||
[[Category: Large Structures]] | |||
[[Category: Unspecific monooxygenase]] | [[Category: Unspecific monooxygenase]] | ||
[[Category: Johnson, E F]] | [[Category: Johnson, E F]] | ||
Revision as of 10:15, 24 February 2021
Crystal Structure Of Human Microsomal P450 2A6 with the inhibitor (5-(Pyridin-3-yl)furan-2-yl)methanamine boundCrystal Structure Of Human Microsomal P450 2A6 with the inhibitor (5-(Pyridin-3-yl)furan-2-yl)methanamine bound
Structural highlights
Function[CP2A6_HUMAN] Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Constitutes the major nicotine C-oxidase. Acts as a 1,4-cineole 2-exo-monooxygenase. Possesses low phenacetin O-deethylation activity.[1] [2] [3] [4] [5] [6] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedA series of 3-heteroaromatic analogues of nicotine were synthesized to delineate structural and mechanistic requirements for selectively inhibiting human cytochrome P450 (CYP) 2A6. Thiophene, substituted thiophene, furan, substituted furan, acetylene, imidazole, substituted imidazole, thiazole, pyrazole, substituted pyrazole, and aliphatic and isoxazol moieties were used to replace the N-methylpyrrolidine ring of nicotine. A number of potent inhibitors were identified, and several exhibited high selectivity for CYP2A6 relative to CYP2E1, -3A4, -2B6, -2C9, -2C19, and -2D6. The majority of these inhibitors elicited type II difference spectra indicating the formation of a coordinate covalent bond to the heme iron. The majority of inhibitors were reversible inhibitors although several mechanism-based inactivators were identified. Most of the inhibitors were also relatively metabolically stable. X-ray crystal structures of CYP2A6 cocrystallized with three furan analogues bearing methanamino side chains indicated that the amine side chain coordinated to the heme iron. The pyridyl moiety was positioned to accept a hydrogen bond from Asn297, and all three inhibitors exhibited orthogonal aromatic-aromatic interactions with protein side chains. For comparison, the cocrystal structure of 4,4'-dipyridyl disulfide was also obtained and showed that the pyridine moiety could assume a different orientation than that observed for the 3-heteroaromatic pyridines examined. For the 3-heteroromatic pyridines, N-methyl and N,N-dimethyl amino groups increased the apparent Ki and distorted helix I of the protein. Substitution of a phenyl ring for the pyridyl ring also increased the apparent Ki, which is likely to reflect the loss of the hydrogen bonding interaction with Asn297. In contrast, inhibitory potency for other P450s was increased, and the selectivity of the phenyl analogues for CYP2A6 was decreased relative to the pyridyl compounds. The results suggest that inhibitors that compliment the active site features of CYP2A6 can exhibit significant selectivity for CYP2A6 relative to other human liver drug-metabolizing P450s. Synthetic inhibitors of cytochrome P-450 2A6: inhibitory activity, difference spectra, mechanism of inhibition, and protein cocrystallization.,Yano JK, Denton TT, Cerny MA, Zhang X, Johnson EF, Cashman JR J Med Chem. 2006 Nov 30;49(24):6987-7001. PMID:17125252[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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