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PDBsum entry 2a4l
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References listed in PDB file
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Key reference
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Title
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Inhibition of cyclin-Dependent kinases by purine analogues: crystal structure of human cdk2 complexed with roscovitine.
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Authors
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W.F.De azevedo,
S.Leclerc,
L.Meijer,
L.Havlicek,
M.Strnad,
S.H.Kim.
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Ref.
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Eur J Biochem, 1997,
243,
518-526.
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PubMed id
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Abstract
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Cyclin-dependent kinases (cdk) control the cell division cycle (cdc). These
kinases and their regulators are frequently deregulated in human tumours. A
potent inhibitor of cdks, roscovitine
[2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurin e], was
identified by screening a series of C2,N6,N9-substituted adenines on purified
cdc2/cyclin B. Roscovitine displays high efficiency and high selectivity
(Meijer, L., Borgne, A., Mulner, O., Chong, J. P. J., Blow, J. J., Inagaki, N.,
Inagaki, M., Delcros, J.-G. & Moulinoux, J.-P. (1997) Eur. J. Biochem. 243,
527-536). It behaves as a competitive inhibitor for ATP binding to cdc2. We
determined the crystal structure of a complex between cdk2 and roscovitine at
0.24-nm (2.4 A) resolution and refined to an Rfactor of 0.18. The purine portion
of the inhibitor binds to the adenine binding pocket of cdk2. The position of
the benzyl ring group of the inhibitor enables the inhibitor to make contacts
with the enzyme not observed in the ATP-complex structure. Analysis of the
position of this benzyl ring explains the specificity of roscovitine in
inhibiting cdk2. The structure also reveals that the (R)-stereoisomer of
roscovitine is bound to cdk2. The (R)-isomer is about twice as potent in
inhibiting cdc2/cyclin B than the (S)-isomer. Results from structure/activity
studies and from analysis of the cdk2/roscovitine complex crystal structure
should allow the design of even more potent cdk inhibitors.
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Secondary reference #1
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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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Secondary reference #2
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Title
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Crystal structure of cyclin-Dependent kinase 2.
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Authors
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H.L.De bondt,
J.Rosenblatt,
J.Jancarik,
H.D.Jones,
D.O.Morgan,
S.H.Kim.
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Ref.
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Nature, 1993,
363,
595-602.
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PubMed id
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