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PDBsum entry 2c5o
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References listed in PDB file
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Key reference
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Title
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Differential binding of inhibitors to active and inactive cdk2 provides insights for drug design.
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Authors
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G.Kontopidis,
C.Mcinnes,
S.R.Pandalaneni,
I.Mcnae,
D.Gibson,
M.Mezna,
M.Thomas,
G.Wood,
S.Wang,
M.D.Walkinshaw,
P.M.Fischer.
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Ref.
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Chem Biol, 2006,
13,
201-211.
[DOI no: ]
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PubMed id
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Abstract
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The cyclin-dependent kinases (CDKs) have been characterized in complex with a
variety of inhibitors, but the majority of structures solved are in the inactive
form. We have solved the structures of six inhibitors in both the monomeric CDK2
and binary CDK2/cyclinA complexes and demonstrate that significant differences
in ligand binding occur depending on the activation state. The binding mode of
two ligands in particular varies substantially in active and inactive CDK2.
Furthermore, energetic analysis of CDK2/cyclin/inhibitors demonstrates that a
good correlation exists between the in vitro potency and the calculated energies
of interaction, but no such relationship exists for CDK2/inhibitor structures.
These results confirm that monomeric CDK2 ligand complexes do not fully reflect
active conformations, revealing significant implications for inhibitor design
while also suggesting that the monomeric CDK2 conformation can be selectively
inhibited.
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Figure 2.
Figure 2. Richardson Diagram of the Overlay of Active and
Inactive apo-CDK2
(A) Active apo-CDK2 is shown in yellow;
inactive apo-CDK2 is shown in blue. The differences in the
orientation of the N and C domains and in the large movement of
the T-loop upon cyclin binding can be observed upon overlay of
the active and inactive structures from residues 170–285.
(B) Electron density difference maps (2F[o] − 1F[c]) in the
ATP binding site of the CDK2/cyclin A/4 complex.
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Figure 3.
Figure 3. Crystal Structures of Ligands 1 and 4 Bound in
Active and Inactive CDK2
(A–C) The overlay shown is
residues 77–143 of the same inhibitor (yellow, active; blue,
inactive) and with the substituted aniline derivative 4 (yellow)
bound in (B) monomeric CDK2 (green) and (C) active (pink) CDK2.
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The above figures are
reprinted
by permission from Cell Press:
Chem Biol
(2006,
13,
201-211)
copyright 2006.
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