2c5o: Difference between revisions
No edit summary |
No edit summary |
||
| Line 5: | Line 5: | ||
==Overview== | ==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 . | 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== | ==About this Structure== | ||
2C5O is a | 2C5O is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with CK2 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Transferred_entry:_2.7.11.1 Transferred entry: 2.7.11.1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.37 2.7.1.37] Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2C5O OCA]. | ||
==Reference== | ==Reference== | ||
| Line 41: | Line 41: | ||
[[Category: transferase]] | [[Category: transferase]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 14:51:34 2007'' | ||
Revision as of 15:46, 5 November 2007
|
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
2C5O is a Protein complex structure of sequences from Homo sapiens with CK2 as ligand. Active as Transferred entry: 2.7.11.1, with EC number 2.7.1.37 Structure known Active Site: AC1. 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 Mon Nov 5 14:51:34 2007
Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Pages with broken file links
- Homo sapiens
- Protein complex
- Transferred entry: 2.7.11.1
- Fischer, P.M.
- Gibson, D.
- Imcnae
- Kontopidis, G.
- Mcinnes, C.
- Mezna, M.
- Pandalaneni, S.R.
- Thomas, M.
- Walkinshaw, M.D.
- Wang, S.
- Wood, G.
- CK2
- Atp-binding
- Cdk2
- Cell cycle
- Cell division
- Cyclin
- Differential inhibition
- Kinase
- Mitosis
- Nucleotide-binding
- Phosphorylation
- Polymorphism
- Serine/threonine-protein
- Transferase