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PDBsum entry 1pxk
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Discovery of a novel family of cdk inhibitors with the program lidaeus: structural basis for ligand-Induced disordering of the activation loop.
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Authors
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S.Y.Wu,
I.Mcnae,
G.Kontopidis,
S.J.Mcclue,
C.Mcinnes,
K.J.Stewart,
S.Wang,
D.I.Zheleva,
H.Marriage,
D.P.Lane,
P.Taylor,
P.M.Fischer,
M.D.Walkinshaw.
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Ref.
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Structure, 2003,
11,
399-410.
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PubMed id
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Abstract
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A family of 4-heteroaryl-2-amino-pyrimidine CDK2 inhibitor lead compounds was
discovered with the new database-mining program LIDAEUS through in silico
screening. Four compounds with IC(50) values ranging from 17 to 0.9 microM were
selected for X-ray crystal analysis. Two distinct binding modes are observed,
one of which resembles the hydrogen bonding pattern of bound ATP. In the second
binding mode, the ligands trigger a conformational change in the activation T
loop by inducing movement of Lys(33) and Asp(145) side chains. The family of
molecules discovered provides an excellent starting point for the design and
synthesis of tight binding inhibitors, which may lead to a new class of
antiproliferative drugs.
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