PDBsum entry 2c5o

Transferase

PDB id: 2c5o

Contents

Protein chains

296 a.a. *

258 a.a. *

Ligands

CK2 ×2

Waters ×725

* Residue conservation analysis

PDB id:

2c5o

Name:

Transferase

Title:

Differential binding of inhibitors to active and inactive cdk2 provides insights for drug design

Structure:

Cell division protein kinase 2. Chain: a, c. Synonym: cyclin-dependent kinase 2, p33 protein kinase. Engineered: yes. Other_details: triazol-1-methyl-pyrimidin inhibitor. Cyclin a2. Chain: b, d. Synonym: cyclin a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expressed in: escherichia coli. Expression_system_taxid: 562

Biol. unit:

Dimer (from PDB file)

Resolution:

2.10Å R-factor: 0.197 R-free: 0.256

Authors:

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

Key ref:

G.Kontopidis et al. (2006). Differential binding of inhibitors to active and inactive CDK2 provides insights for drug design. Chem Biol, 13, 201-211. PubMed id: 16492568 DOI: 10.1016/j.chembiol.2005.11.011

Date:

30-Oct-05 Release date: 01-Mar-06

Protein chains

P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2 from Homo sapiens

Seq: 298 a.a.

Struc: 296 a.a.

Protein chains

P20248  (CCNA2_HUMAN) -  Cyclin-A2 from Homo sapiens

Seq: 432 a.a.

Struc: 258 a.a.

Enzyme reactions

• Enzyme class: Chains A, C: E.C.2.7.11.22 - cyclin-dependent kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.chembiol.2005.11.011

Chem Biol 13:201-211 (2006)

PubMed id: 16492568

Differential binding of inhibitors to active and inactive CDK2 provides insights for drug design.

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.

ABSTRACT

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.

Selected figure(s)

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.

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.

The above figures are reprinted by permission from Cell Press: Chem Biol (2006, 13, 201-211) copyright 2006.

Figures were selected by an automated process.