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Conformational Adaptation of Human Cytochrome P450 2B6 and Rabbit Cytochrome P450 2B4 Revealed upon Binding Multiple Amlodipine Molecules

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Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, United States
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, United States
§ Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, United States
*E-mail: [email protected]. Telephone: (858) 822-7804. Fax: (858) 246-0089.
Cite this: Biochemistry 2012, 51, 37, 7225–7238
Publication Date (Web):August 21, 2012
https://doi.org/10.1021/bi300894z
Copyright © 2012 American Chemical Society

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    Abstract

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    Structures of human cytochrome P450 2B6 and rabbit cytochrome P450 2B4 in complex with two molecules of the calcium channel blocker amlodipine have been determined by X-ray crystallography. The presence of two drug molecules suggests clear substrate access channels in each P450. According to a previously established nomenclature, amlodipine molecules were trapped in access pathway 2f in P450 2B6 and in pathway 2a or 2f in P450 2B4. These pathways overlap for part of the length and then diverge as they extend toward the protein surface. A previously described solvent channel was also found in each enzyme. The results indicate that key residues located on the surface and at the entrance of the substrate access channels in each of these P450s may play a crucial role in guiding substrate entry. In addition, the region of P450 2B6 and 2B4 involving helices B′, F, F′, and G′ and part of helix G is substantially more open in the amlodipine complexes than in the corresponding 4-(4-chlorophenyl)imidazole complexes. The increased active site volume observed results from the major retraction of helices F, F′, and B′ and the β4 sheet region located close to the binding cavity to accommodate amlodipine. These structures demonstrate novel insight into distinct conformational states not observed with previous P450 2B structures and provide clear evidence of the substrate access channels in two drug-metabolizing P450s. In addition, the structures exhibit the versatility that can be exploited via in silico studies with other P450 2B6 ligands as large as raloxifene and itraconazole.

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    The initial P450 2B4 X-ray crystal structure was determined using a truncated and modified protein containing the wild-type His226. Because of the formation of a dimer involving coordination of His226 of each monomer with the heme iron of the other monomer, subsequent biochemical and crystallography work utilized the H226Y mutant. In this work, P450 2B4 will refer to P450 2B4dH(H226Y) unless otherwise stated.

    P450 2B6 stands for an N-terminally truncated and modified and C-terminally His-tagged form of the cytochrome P450 2B6 genetic variant K262R with an internal Y226H mutation.

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    Table showing the active site residues located within 5 Å of amlodipine molecules in P450 2B4 and P450 2B6, a diagram showing the amlodipine structure, a, figure showing an orthogonal stereoview of amlodipine electron density in P450 2B4 and P450 2B6 complexes, figures showing the residues lining the solvent channel in P450 2B4 and P450 2B6 and an overlay with the corresponding 4-CPI complexes, an overlay of P450 2B6 and P450 2B4 structures showing differences near the C-terminal region, an overlay of P450 2B4– and P450 2B6–amlodipine complexes, structures of P450 2B4 and P450 2B6 showing interactions with amlodipine, a difference spectrum of P450 2B4 representative of a type II change upon amlodipine binding, an overlay of the P450 2B4–amlodipine complex with the P450 2A13–NNK structure, an overlay of various P450 2B4 and P450 2B6 complexes showing the location of the CYMAL-5 molecule at the 2f substrate access channel entrance, figures showing an overlay of the P450 2B4–amlodipine complex with the P450 2B4–bifonazole and P450–1PBI complexes, and an overlay of P450 2B4– and P450 2B6–amlodipine and 4-CPI complexes showing the location of residue E218. This material is available free of charge via the Internet at http://pubs.acs.org.

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