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Title
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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.
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Authors
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S.C.Gay,
L.Sun,
K.Maekawa,
J.R.Halpert,
C.D.Stout.
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Ref.
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Biochemistry, 2009,
48,
4762-4771.
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PubMed id
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Abstract
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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.
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