3UA5

Crystal Structure of P450 2B6 (Y226H/K262R) in complex with two molecules of Amlodipine

Summary for 3UA5

• Entry DOI: 10.2210/pdb3ua5/pdb
• Related: 3IBD 3QOA 3QU8
• Descriptor: Cytochrome P450 2B6, PROTOPORPHYRIN IX CONTAINING FE, Amlodipine, ... (4 entities in total)
• Functional Keywords: p450, human cytochrome p450 2b6, monooxygenase, oxidoreductase, membrane protein, cyp 2b6
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum membrane; Peripheral membrane protein: P20813
• Total number of polymer chains: 2
• Total formula weight: 112160.49

Authors

Shah, M.B.,Stout, C.D.,Halpert, J.R. (deposition date: 2011-10-21, release date: 2012-09-12, Last modification date: 2023-09-13)

Primary citation

Shah, M.B.,Wilderman, P.R.,Pascual, J.,Zhang, Q.,Stout, C.D.,Halpert, J.R.
Conformational Adaptation of Human Cytochrome P450 2B6 and Rabbit Cytochrome P450 2B4 Revealed upon Binding Multiple Amlodipine Molecules.
Biochemistry, 51:7225-7238, 2012

PubMed Abstract: 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.

PubMed: 22909231
DOI: 10.1021/bi300894z

Experimental method

X-RAY DIFFRACTION (2.8 Å)