3G93

Single ligand occupancy crystal structure of cytochrome P450 2B4 in complex with the inhibitor 1-biphenyl-4-methyl-1H-imidazole

Summary for 3G93

• Entry DOI: 10.2210/pdb3g93/pdb
• Related: 1PO5 1SUO 2BDM 2Q6N 3G5N
• Descriptor: Cytochrome P450 2B4, PROTOPORPHYRIN IX CONTAINING FE, 1-(biphenyl-4-ylmethyl)-1H-imidazole, ... (4 entities in total)
• Functional Keywords: p450, cytochrome p450 2b4, monooxygenase, oxidoreductase, membrane protein, cyp 2b4, cyp lm2, endoplasmic reticulum, heme, iron, membrane, metal-binding, microsome, phosphoprotein, polymorphism
• Biological source: Oryctolagus cuniculus (European rabbit,Japanese white rabbit,domestic rabbit,rabbits)
• Cellular location: Endoplasmic reticulum membrane; Peripheral membrane protein: P00178
• Total number of polymer chains: 4
• Total formula weight: 220079.46

Authors

Gay, S.C.,Sun, L.,Maekawa, K.,Halpert, J.R.,Stout, C.D. (deposition date: 2009-02-12, release date: 2009-05-12, Last modification date: 2023-09-06)

Primary citation

Gay, S.C.,Sun, L.,Maekawa, K.,Halpert, J.R.,Stout, C.D.
Crystal structures of cytochrome P450 2B4 in complex with the inhibitor 1-biphenyl-4-methyl-1H-imidazole: ligand-induced structural response through alpha-helical repositioning.
Biochemistry, 48:4762-4771, 2009

PubMed Abstract: Two different ligand occupancy structures of cytochrome P450 2B4 (CYP2B4) in complex with 1-biphenyl-4-methyl-1H-imidazole (1-PBI) have been determined by X-ray crystallography. 1-PBI belongs to a series of tight binding, imidazole-based CYP2B4 inhibitors. 1-PBI binding to CYP2B4 yields a type II spectrum with a K(s) value of 0.23 microM and inhibits enzyme activity with an IC(50) value of 0.035 microM. Previous CYP2B4 structures have shown a large degree of structural movement in response to ligand size. With two phenyl rings, 1-PBI is larger than 1-(4-chlorophenyl)imidazole (1-CPI) and 4-(4-chlorophenyl)imidazole (4-CPI) but smaller than bifonazole, which is branched and contains three phenyl rings. The CYP2B4-1-PBI complex is a structural intermediate to the closed CPI and the open bifonazole structures. The B/C-loop reorganizes itself to include two short partial helices while closing one side of the active site. The F-G-helix cassette pivots over the I-helix in direct response to the size of the ligand in the active site. A cluster of Phe residues at the fulcrum of this pivot point allows for dramatic repositioning of the cassette with only a relatively small amount of secondary structure rearrangement. Comparisons of ligand-bound CYP2B4 structures reveal trends in plastic region mobility that could allow for predictions of their position in future structures based on ligand shape and size.

PubMed: 19397311
DOI: 10.1021/bi9003765

Experimental method

X-RAY DIFFRACTION (3.2 Å)