2c5n: Difference between revisions

Revision as of 17:45, 21 February 2008

DIFFERENTIAL BINDING OF INHIBITORS TO ACTIVE AND INACTIVE CDK2 PROVIDES INSIGHTS FOR DRUG DESIGN

OverviewOverview

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.

About this StructureAbout this Structure

2C5N is a Protein complex structure of sequences from Homo sapiens with as ligand. Active as Transferred entry: 2.7.11.1, with EC number 2.7.1.37 Known structural/functional Site: . Full crystallographic information is available from OCA.

ReferenceReference

Differential binding of inhibitors to active and inactive CDK2 provides insights for drug design., Kontopidis G, McInnes C, Pandalaneni SR, McNae I, Gibson D, Mezna M, Thomas M, Wood G, Wang S, Walkinshaw MD, Fischer PM, Chem Biol. 2006 Feb;13(2):201-11. PMID:16492568

Page seeded by OCA on Thu Feb 21 16:45:22 2008

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OCA

@@ Line 4: / Line 4: @@
 ==Overview==
-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.
+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.
 ==About this Structure==
@@ Line 13: / Line 13: @@
 [[Category: Homo sapiens]]
 [[Category: Protein complex]]
-[[Category: Transferred entry: 2.7.11.1]]
+[[Category: Transferred entry: 2 7.11 1]]
-[[Category: Fischer, P.M.]]
+[[Category: Fischer, P M.]]
 [[Category: Gibson, D.]]
 [[Category: Kontopidis, G.]]
@@ Line 20: / Line 20: @@
 [[Category: Mcnae, I.]]
 [[Category: Mezna, M.]]
-[[Category: Pandalaneni, S.R.]]
+[[Category: Pandalaneni, S R.]]
 [[Category: Thomas, M.]]
-[[Category: Walkinshaw, M.D.]]
+[[Category: Walkinshaw, M D.]]
 [[Category: Wang, S.]]
 [[Category: Wood, G.]]
@@ Line 40: / Line 40: @@
 [[Category: transferase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Feb  3 10:31:47 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:45:22 2008''