PT  - JOURNAL ARTICLE
AU  - Manish B. Shah
AU  - Irina Kufareva
AU  - Jaime Pascual
AU  - Qinghai Zhang
AU  - C. David Stout
AU  - James R. Halpert
TI  - A Structural Snapshot of CYP2B4 in Complex with Paroxetine Provides Insights into Ligand Binding and Clusters of Conformational States
AID  - 10.1124/jpet.113.204776
DP  - 2013 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 113--120
VI  - 346
IP  - 1
4099  - http://jpet.aspetjournals.org/content/346/1/113.short
4100  - http://jpet.aspetjournals.org/content/346/1/113.full
SO  - J Pharmacol Exp Ther2013 Jul 01; 346
AB  - 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.