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Title
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Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase.
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Authors
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W.F.De Azevedo,
H.J.Mueller-Dieckmann,
U.Schulze-Gahmen,
P.J.Worland,
E.Sausville,
S.H.Kim.
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Ref.
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Proc Natl Acad Sci U S A, 1996,
93,
2735-2740.
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PubMed id
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Abstract
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The central role of cyclin-dependent kinases (CDKs) in cell cycle regulation
makes them a promising target for studying inhibitory molecules that can modify
the degree of cell proliferation. The discovery of specific inhibitors of CDKs
such as polyhydroxylated flavones has opened the way to investigation and design
of antimitotic compounds. A novel flavone,
(-)-cis-5,7-dihydroxyphenyl-8-[4-(3-hydroxy-1-methyl)piperidinyl]
-4H-1-benzopyran-4-one hydrochloride hemihydrate (L868276), is a potent
inhibitor of CDKs. A chlorinated form, flavopiridol, is currently in phase I
clinical trials as a drug against breast tumors. We determined the crystal
structure of a complex between CDK2 and L868276 at 2.33 angstroms resolution and
refined to an Rfactor 20.3%. The aromatic portion of the inhibitor binds to the
adenine-binding pocket of CDK2, and the position of the phenyl group of the
inhibitor enables the inhibitor to make contacts with the enzyme not observed in
the ATP complex structure. The analysis of the position of this phenyl ring not
only explains the great differences of kinase inhibition among the flavonoid
inhibitors but also explains the specificity of L868276 to inhibit CDK2 and CDC2.
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