A Structural Snapshot of Cytochrome P450 2B4 in Complex with Paroxetine Provides Insights into Ligand Binding and Clusters of Conformational States.
An X-ray crystal structure of cytochrome P450 2B4 in complex with the drug paroxetine was solved at 2.14 Å resolution. The structure revealed a conformation intermediate to that of the recently solved complex with amlodipine and of the more compact complex with 4-(4-chlorophenyl)imidazole in terms of the placement of the F-G cassette. Moreover, the comparison of the new structure with 15 previously solved structures of P450 2B4 revealed some new insights into 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 sub-chamber that resulted from the movement of secondary structural elements and rearrangements of active site side chains. Overall, the results from the comparison of all the 16 structures of P450 2B4 demonstrate a cluster of protein conformations that were observed in the presence or absence of various ligands.
T10 T11 T1 T2 T3 T4 T5 T6 T7 T8 T9
GENE-Y GENE-Y CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-Y GENE-Y GENE-Y
2B4 Cytochrome P450 2B4 amlodipine 4-(4-chlorophenyl)imidazole paroxetine paroxetine paroxetine Paroxetine P450 2B4 cytochrome P450 2B4 P450 2B4