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PDBsum entry 2c5o

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protein ligands Protein-protein interface(s) links
Transferase PDB id
2c5o
Jmol
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:
2.1Å     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    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
Seq:
Struc:
298 a.a.
296 a.a.
Protein chains
Pfam   ArchSchema ?
P20248  (CCNA2_HUMAN) -  Cyclin-A2
Seq:
Struc:
432 a.a.
258 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains A, C: E.C.2.7.11.22  - Cyclin-dependent kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
= ADP
+ phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cyclin-dependent protein kinase holoenzyme complex   15 terms 
  Biological process     regulation of gene silencing   30 terms 
  Biochemical function     nucleotide binding     13 terms  

 

 
    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.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21364740 A.De Biasio, R.Sánchez, J.Prieto, M.Villate, R.Campos-Olivas, and F.J.Blanco (2011).
Reduced Stability and Increased Dynamics in the Human Proliferating Cell Nuclear Antigen (PCNA) Relative to the Yeast Homolog.
  PLoS One, 6, e16600.  
21244636 N.Zhang, R.Zhong, H.Yan, and Y.Jiang (2011).
Structural features underlying selective inhibition of GSK3β by dibromocantharelline: implications for rational drug design.
  Chem Biol Drug Des, 77, 199-205.  
19472269 G.Kontopidis, M.J.Andrews, C.McInnes, A.Plater, L.Innes, S.Renachowski, A.Cowan, and P.M.Fischer (2009).
Truncation and optimisation of peptide inhibitors of cyclin-dependent kinase 2-cyclin a through structure-guided design.
  ChemMedChem, 4, 1120-1128.
PDB codes: 2wev 2wfy 2whb
19274736 H.Zhang, T.Zhang, K.Chen, S.Shen, J.Ruan, and L.Kurgan (2009).
On the relation between residue flexibility and local solvent accessibility in proteins.
  Proteins, 76, 617-636.  
18037921 P.Taylor, E.Blackburn, Y.G.Sheng, S.Harding, K.Y.Hsin, D.Kan, S.Shave, and M.D.Walkinshaw (2008).
Ligand discovery and virtual screening using the program LIDAEUS.
  Br J Pharmacol, 153, S55-S67.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.