5e58 | pdb_00005e58

Crystal Structure Of Cytochrome P450 2B35 from Desert Woodrat Neotoma Lepida in complex with 4-(4-chlorophenyl)imidazole

spinqualitylabelsall models 5e58, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5e58 is a 6 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CM5, CPZ, GOL, HEM, SUC Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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