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Title
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Structures of cytochrome P450 2B4 complexed with the antiplatelet drugs ticlopidine and clopidogrel .
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Authors
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S.C.Gay,
A.G.Roberts,
K.Maekawa,
J.C.Talakad,
W.X.Hong,
Q.Zhang,
C.D.Stout,
J.R.Halpert.
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Ref.
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Biochemistry, 2010,
49,
8709-8720.
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PubMed id
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Abstract
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Prior X-ray crystal structures of rabbit cytochrome P450 2B4 (2B4) in complexes
with various imidazoles have demonstrated markedly different enzyme
conformations depending on the size of the inhibitor occupying the active site.
In this study, structures of 2B4 were determined with the antiplatelet drugs
clopidogrel and ticlopidine, which were expected to have greater freedom of
movement in the binding pocket. Ticlopidine could be modeled into the electron
density maps in two distinct orientations, both of which are consistent with
metabolic data gathered with other mammalian P450 enzymes. Results of ligand
docking and heme-induced NMR relaxation of drug protons showed that ticlopidine
was preferentially oriented with the chlorophenyl group closest to the heme.
Because of its stereocenter, clopidogrel was easier to fit in the electron
density and exhibited a single orientation, which points the chlorophenyl ring
toward the heme. The C(α) traces of both complexes aligned very well with each
other and revealed a compact, closed structure that resembles the conformation
observed in two previously determined 2B4 structures with the small molecule
inhibitors 4-(4-chlorophenyl)imidazole and 1-(4-chlorophenyl)imidazole. The 2B4
active site is able to accommodate small ligands by moving only a small number
of side chains, suggesting that ligand reorientation is energetically favored
over protein conformational changes for binding of these similarly sized
molecules. Adjusting both protein conformation and ligand orientation in the
active site gives 2B4 the flexibility to bind to the widest range of molecules,
while also being energetically favorable.
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