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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Amino Acid Substitution
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Animals
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Antidepressive Agents, Second-Generation / chemistry*
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Antidepressive Agents, Second-Generation / metabolism
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Antidepressive Agents, Second-Generation / pharmacology
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Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors
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Aryl Hydrocarbon Hydroxylases / chemistry*
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Aryl Hydrocarbon Hydroxylases / genetics
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Aryl Hydrocarbon Hydroxylases / metabolism
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Catalytic Domain / drug effects
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Crystallography, X-Ray
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Cytochrome P-450 Enzyme Inhibitors
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Cytochrome P-450 Enzyme System / chemistry
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Cytochrome P-450 Enzyme System / genetics
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Cytochrome P-450 Enzyme System / metabolism
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Cytochrome P450 Family 2
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Databases, Protein
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacology
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Ligands
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Models, Molecular*
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Molecular Conformation / drug effects
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Mutant Proteins / antagonists & inhibitors
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Mutant Proteins / chemistry
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Mutant Proteins / genetics
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Mutant Proteins / metabolism
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Paroxetine / chemistry*
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Paroxetine / metabolism
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Paroxetine / pharmacology
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Peptide Fragments / antagonists & inhibitors
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Peptide Fragments / chemistry
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Peptide Fragments / genetics
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Peptide Fragments / metabolism
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Protein Binding
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Protein Structure, Secondary / drug effects
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Rabbits
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Rats
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Selective Serotonin Reuptake Inhibitors / chemistry
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Selective Serotonin Reuptake Inhibitors / metabolism
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Selective Serotonin Reuptake Inhibitors / pharmacology
Substances
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Antidepressive Agents, Second-Generation
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Cytochrome P-450 Enzyme Inhibitors
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Enzyme Inhibitors
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Ligands
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Mutant Proteins
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Peptide Fragments
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Recombinant Proteins
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Serotonin Uptake Inhibitors
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Paroxetine
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Cytochrome P-450 Enzyme System
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cytochrome P-450 CYP2B4, rat
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Aryl Hydrocarbon Hydroxylases
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Cytochrome P450 Family 2
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cytochrome P-450 CYP2B4 (rabbit)