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Conformational plasticity of cytochrome P450 2B4: crystallographic and solution studies
Author(s) -
Zhao Yonghong,
White Mark A.,
Muralidhara B. K.,
Sun Ling,
Stout C. David,
Halpert James R.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a659
Subject(s) - chemistry , crystallography , plasticity , materials science , composite material
Cytochromes P450 are the most important oxidative enzymes involved in xenobiotic metabolism. Understanding the structural basis of P450‐ligand interactions is a prerequisite for evaluating and predicting the metabolism of drugs. A crystal structure of cytochrome P450 2B4 bound with the antifungal drug bifonazole reveals an active site cleft that is widely open in the middle but narrow at the top. A bifonazole molecule occupies the bottom of the active site cleft where helix I is bent ~15° to accommodate the ligand. The O‐shaped active site cleft of 2B4‐bifonazole is very different from the previously determined structures of ligand‐free 2B4 and 2B4 bound with the smaller inhibitor 4‐(4‐chlorophenyl)imidazole (CPI). Comparison of the three 2B4 structures identified structurally conserved regions and structurally flexible regions, providing new insight into structural plasticity of the enzyme. Isothermal titration calorimetry and fluorescence quenching experiments indicated that the conformation of 2B4‐bifonazole is different from that of 2B4‐CPI in solution. These results demonstrated that 2B4 can adopt strikingly different conformations in order to reshape its active site to accommodate ligands of different size. [Supported by National Institutes of Health grants ES03619 (to J.R.H.), GM61545 (to C.D.S.), and Center grant ES06676 (to J.R.H.)].