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Title
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Multiple modes of ligand recognition: crystal structures of cyclin-dependent protein kinase 2 in complex with ATP and two inhibitors, olomoucine and isopentenyladenine.
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Authors
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U.Schulze-Gahmen,
J.Brandsen,
H.D.Jones,
D.O.Morgan,
L.Meijer,
J.Vesely,
S.H.Kim.
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Ref.
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Proteins, 1995,
22,
378-391.
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PubMed id
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Abstract
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Cyclin-dependent kinases (CDKs) are conserved regulators of the eukaryotic cell
cycle with different isoforms controlling specific phases of the cell cycle.
Mitogenic or growth inhibitory signals are mediated, respectively, by activation
or inhibition of CDKs which phosphorylate proteins associated with the cell
cycle. The central role of CDKs in cell cycle regulation makes them a potential
new target for inhibitory molecules with anti-proliferative and/or
anti-neoplastic effects. We describe the crystal structures of the complexes of
CDK2 with a weakly specific CDK inhibitor, N6-(delta 2-isopentenyl)adenine, and
a strongly specific inhibitor, olomoucine. Both inhibitors are adenine
derivatives and bind in the adenine binding pocket of CDK2, but in an unexpected
and different orientation from the adenine of the authentic ligand ATP. The
N6-benzyl substituent in olomoucine binds outside the conserved binding pocket
and is most likely responsible for its specificity. The structural information
from the CDK2-olomoucine complex will be useful in directing the search for the
next generation inhibitors with improved properties.
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