title: A structural snapshot of CYP2B4 in complex with paroxetine provides insights into ligand binding and clusters of conformational states.
abstract: An X-ray crystal structure of CYP2B4 in complex with the drug paroxetine [(3S,4R)-3-[(2H-1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine] was solved at 2.14 Å resolution. The structure revealed a conformation intermediate to that of the recently solved complex with amlodipine and that of the more compact complex with 4-(4-chlorophenyl)imidazole in terms of the placement of the F-G cassette. Moreover, comparison of the new structure with 15 previously solved structures of CYP2B4 revealed some new insights into the determinants of active-site size and shape. The 2B4-paroxetine structure is nearly superimposable on a previously solved closed structure in a ligand-free state. Despite the overall conformational similarity among multiple closed structures, the active-site cavity volume of the paroxetine complex is enlarged. Further analysis of the accessible space and binding pocket near the heme reveals a new subchamber that resulted from the movement of secondary structural elements and rearrangements of active-site side chains. Overall, the results from the comparison of all 16 structures of CYP2B4 demonstrate a cluster of protein conformations that were observed in the presence or absence of various ligands.
authors: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, Mail Code 0703, La Jolla, CA 92093-0703, USA. m7shah@ucsd.edu
authors: Manish B
authors: MB
authors: Shah
authors: Irina
authors: I
authors: Kufareva
authors: Jaime
authors: J
authors: Pascual
authors: Qinghai
authors: Q
authors: Zhang
authors: C David
authors: CD
authors: Stout
authors: James R
authors: JR
authors: Halpert
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020134:Catalytic Domain / Q000187:drug effects; D018360:Crystallography, X-Ray; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D030562:Databases, Protein; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation / Q000187:drug effects; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017374:Paroxetine / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D018687:Antidepressive Agents, Second-Generation; D001189:Aryl Hydrocarbon Hydroxylases; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D000072467:Cytochrome P450 Family 2; D004791:Enzyme Inhibitors; D008024:Ligands; D050505:Mutant Proteins; D017374:Paroxetine; D010446:Peptide Fragments; D011994:Recombinant Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C583129:cytochrome P-450 CYP2B4, rat; C465241:cytochrome P-450 CYP2B4 (rabbit)
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