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| | <StructureSection load='5e0e' size='340' side='right'caption='[[5e0e]], [[Resolution|resolution]] 3.40Å' scene=''> | | <StructureSection load='5e0e' size='340' side='right'caption='[[5e0e]], [[Resolution|resolution]] 3.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5e0e]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Desert_woodrat Desert woodrat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5E0E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5E0E FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5e0e]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Neotoma_lepida Neotoma lepida]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5E0E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5E0E FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CPZ:4-(4-CHLOROPHENYL)IMIDAZOLE'>CPZ</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.4Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP2B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=56216 Desert woodrat])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CPZ:4-(4-CHLOROPHENYL)IMIDAZOLE'>CPZ</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5e0e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5e0e OCA], [http://pdbe.org/5e0e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5e0e RCSB], [http://www.ebi.ac.uk/pdbsum/5e0e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5e0e ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5e0e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5e0e OCA], [https://pdbe.org/5e0e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5e0e RCSB], [https://www.ebi.ac.uk/pdbsum/5e0e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5e0e ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/J9JD75_NEOLE J9JD75_NEOLE] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Desert woodrat]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Halpert, J R]] | + | [[Category: Neotoma lepida]] |
| - | [[Category: Shah, M B]] | + | [[Category: Halpert JR]] |
| - | [[Category: Stout, C D]] | + | [[Category: Shah MB]] |
| - | [[Category: Cyp2b37]] | + | [[Category: Stout CD]] |
| - | [[Category: Cytochrome p450]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
| + | |
| Structural highlights
Function
J9JD75_NEOLE
Publication Abstract from PubMed
Crystal structures of CYP2B35 and CYP2B37 from the desert woodrat were solved in complex with 4-(4-chlorophenyl) imidazole (4-CPI). The closed conformation of CYP2B35 contained two molecules of 4-CPI within the active site, whereas the CYP2B37 structure demonstrated an open conformation with three 4-CPI molecules, one within the active site and the other two in the substrate access channel. To probe structure-function relationships of CYP2B35, CYP2B37, and the related CYP2B36 we tested the O-dealkylation of three series of related substrates, namely 7-alkoxycoumarins, 7-alkoxy-4-(trifluoromethyl)coumarins, and 7-alkoxy-4-methylcoumarins with a C1-C7 side chain. CYP2B35 showed the highest catalytic efficiency (kcat/KM) with 7-heptoxycoumarin as a substrate, followed by 7-hexoxycoumarin. In contrast, CYP2B37 showed the highest catalytic efficiency with 7-ethoxy-4-(trifluoromethyl)coumarin (7-EFC), followed by 7-methoxy-4-(trifluoromethyl)coumarin (7-MFC). CYP2B35 had no dealkylation activity with 7-MFC or 7-EFC. Furthermore, the new CYP2B-4-CPI bound structures were used as templates for docking the 7-substituted coumarin derivatives, which revealed orientations consistent with the functional studies. In addition, the observation of multiple -Cl and -NH-pi interactions of 4-CPI with the aromatic side chains in the CYP2B35 and CYP2B37 structures provide insight into the influence of such functional groups on CYP2B-ligand binding affinity and specificity. To conclude, structural, computational, and functional analysis revealed striking differences between the active sites of CYP2B35 and CYP2B37 that will aid in the elucidation of new structure-activity relationships.
Structure-Function Analysis of Mammalian CYP2B Enzymes using 7-Substituted Coumarin Derivatives as Probes: Utility of Crystal Structures and Molecular Modeling in Understanding Xenobiotic Metabolism.,Shah MB, Liu J, Huo L, Zhang Q, Dearing MD, Wilderman PR, Szklarz GD, Stout CD, Halpert JR Mol Pharmacol. 2016 Jan 29. pii: mol.115.102111. PMID:26826176[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Shah MB, Liu J, Huo L, Zhang Q, Dearing MD, Wilderman PR, Szklarz GD, Stout CD, Halpert JR. Structure-Function Analysis of Mammalian CYP2B Enzymes using 7-Substituted Coumarin Derivatives as Probes: Utility of Crystal Structures and Molecular Modeling in Understanding Xenobiotic Metabolism. Mol Pharmacol. 2016 Jan 29. pii: mol.115.102111. PMID:26826176 doi:http://dx.doi.org/10.1124/mol.115.102111
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