2NNI

CYP2C8dH complexed with montelukast

Summary for 2NNI

• Entry DOI: 10.2210/pdb2nni/pdb
• Related: 2NNH 2NNJ
• Descriptor: Cytochrome P450 2C8, SULFATE ION, PROTOPORPHYRIN IX CONTAINING FE, ... (6 entities in total)
• Functional Keywords: cyp2c8; human p450 2c8; monooxygenases; montelukast; singulair; inhibitor complex; palmitic aci, oxidoreductase, electron transport
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum membrane; Peripheral membrane protein: P10632
• Total number of polymer chains: 1
• Total formula weight: 55609.31

Authors

Schoch, G.A.,Yano, J.K.,Stout, C.D.,Johnson, E.F. (deposition date: 2006-10-24, release date: 2007-10-23, Last modification date: 2023-08-30)

Primary citation

Schoch, G.A.,Yano, J.K.,Sansen, S.,Dansette, P.M.,Stout, C.D.,Johnson, E.F.
Determinants of cytochrome P450 2C8 substrate binding: structures of complexes with montelukast, troglitazone, felodipine, and 9-cis-retinoic acid.
J.Biol.Chem., 283:17227-17237, 2008

PubMed Abstract: Although a crystal structure and a pharmacophore model are available for cytochrome P450 2C8, the role of protein flexibility and specific ligand-protein interactions that govern substrate binding are poorly understood. X-ray crystal structures of P450 2C8 complexed with montelukast (2.8 A), troglitazone (2.7 A), felodipine (2.3 A), and 9-cis-retinoic acid (2.6 A) were determined to examine ligand-protein interactions for these chemically diverse compounds. Montelukast is a relatively large anionic inhibitor that exhibits a tripartite structure and complements the size and shape of the active-site cavity. The inhibitor troglitazone occupies the upper portion of the active-site cavity, leaving a substantial part of the cavity unoccupied. The smaller neutral felodipine molecule is sequestered with its dichlorophenyl group positioned close to the heme iron, and water molecules fill the distal portion of the cavity. The structure of the 9-cis-retinoic acid complex reveals that two substrate molecules bind simultaneously in the active site of P450 2C8. A second molecule of 9-cis-retinoic acid is located above the proximal molecule and can restrain the position of the latter for more efficient oxygenation. Solution binding studies do not discriminate between cooperative and noncooperative models for multiple substrate binding. The complexes with structurally distinct ligands further demonstrate the conformational adaptability of active site-constituting residues, especially Arg-241, that can reorient in the active-site cavity to stabilize a negatively charged functional group and define two spatially distinct binding sites for anionic moieties of substrates.

PubMed: 18413310
DOI: 10.1074/jbc.M802180200

Experimental method

X-RAY DIFFRACTION (2.8 Å)