PDBsum entry 1okw

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Transferase/transferase inhibitor PDB id
Protein chains
296 a.a. *
258 a.a. *
Waters ×539
* Residue conservation analysis
PDB id:
Name: Transferase/transferase inhibitor
Title: Cyclin a binding groove inhibitor ac-arg-arg-leu-asn-(m-cl-p
Structure: Cell division protein kinase 2. Chain: a, c. Synonym: cyclin-dependent kinase 2, p33 protein kinase. Engineered: yes. Cyclin a2. Chain: b, d. Fragment: residues 173 - 432. 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. Synthetic: yes
Biol. unit: Trimer (from PDB file)
2.50Å     R-factor:   0.175     R-free:   0.253
Authors: G.Kontopidis,M.Andrews,C.Mcinnes,A.Cowan,H.Powers,L.Innes,A. G.Griffiths,D.Paterson,D.Zheleva,D.Lane,S.Green,M.Walkinsha P.Fischer
Key ref:
G.Kontopidis et al. (2003). Insights into cyclin groove recognition: complex crystal structures and inhibitor design through ligand exchange. Structure, 11, 1537-1546. PubMed id: 14656438 DOI: 10.1016/j.str.2003.11.006
31-Jul-03     Release date:   11-Dec-03    
Go to PROCHECK summary

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

 Enzyme reactions 
   Enzyme class: Chains A, C: E.C.  - Cyclin-dependent kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
+ protein
+ 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   31 terms 
  Biochemical function     nucleotide binding     13 terms  


DOI no: 10.1016/j.str.2003.11.006 Structure 11:1537-1546 (2003)
PubMed id: 14656438  
Insights into cyclin groove recognition: complex crystal structures and inhibitor design through ligand exchange.
G.Kontopidis, M.J.Andrews, C.McInnes, A.Cowan, H.Powers, L.Innes, A.Plater, G.Griffiths, D.Paterson, D.I.Zheleva, D.P.Lane, S.Green, M.D.Walkinshaw, P.M.Fischer.
Inhibition of CDK2/CA (cyclin-dependent kinase 2/cyclin A complex) activity through blocking of the substrate recognition site in the cyclin A subunit has been demonstrated to be an effective method for inducing apoptosis in tumor cells. We have used the cyclin binding motif (CBM) present in the tumor suppressor proteins p21(WAF1) and p27(KIP1) as a template to optimize the minimal sequence necessary for CDK2/CA inhibition. A series of peptides were prepared, containing nonnatural amino acids, which possess nano- to micromolar CDK2-inhibitory activity. Here we present X-ray structures of the protein complex CDK2/CA, together with the cyclin groove-bound peptides H-Ala-Ala-Abu-Arg-Ser-Leu-Ile-(p-F-Phe)-NH(2) (peptide 1), H-Arg-Arg-Leu-Ile-Phe-NH(2) (peptide 2), Ac-Arg-Arg-Leu-Asn-(m-Cl-Phe)-NH(2) (peptide 3), H-Arg-Arg-Leu-Asn-(p-F-Phe)-NH(2) (peptide 4), and H-Cit-Cit-Leu-Ile-(p-F-Phe)-NH(2) (peptide 5). Some of the peptide complexes presented here were obtained through the novel technique of ligand exchange within protein crystals. This method may find general application for obtaining complex structures of proteins with surface-bound ligands.
  Selected figure(s)  
Figure 3.
Figure 3. The Electron Density Maps of Peptides 1-5The 2F[o] - 1F[c] maps are contoured at a level corresponding to 1.2 s for the peptides bound to the nonoccluded cyclin groove.(A) Superimposition of the structures of peptide 2 in the free (yellow) and partially occluded (green) CBG shows the differences of the two copies of the peptide.(B) Overlay of the bound conformations of peptides 1 (gray), 2 (green), 3 (red), 4 (CPK coloring), and 5 (magenta).
  The above figure is reprinted by permission from Cell Press: Structure (2003, 11, 1537-1546) copyright 2003.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20656489 M.M.Maslon, and T.R.Hupp (2010).
Drug discovery and mutant p53.
  Trends Cell Biol, 20, 542-555.  
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
19296866 L.N.Johnson (2009).
Protein kinase inhibitors: contributions from structure to clinical compounds.
  Q Rev Biophys, 42, 1.  
19039815 M.Orzáez, A.Gortat, L.Mondragón, O.Bachs, and E.Pérez-Payá (2009).
ATP-noncompetitive inhibitors of CDK-cyclin complexes.
  ChemMedChem, 4, 19-24.  
17705877 N.Sugaya, K.Ikeda, T.Tashiro, S.Takeda, J.Otomo, Y.Ishida, A.Shiratori, A.Toyoda, H.Noguchi, T.Takeda, S.Kuhara, Y.Sakaki, and T.Iwayanagi (2007).
An integrative in silico approach for discovering candidates for drug-targetable protein-protein interactions in interactome data.
  BMC Pharmacol, 7, 10.  
16584130 J.Sridhar, N.Akula, and N.Pattabiraman (2006).
Selectivity and potency of cyclin-dependent kinase inhibitors.
  AAPS J, 8, E204-E221.  
17051658 M.J.Andrews, G.Kontopidis, C.McInnes, A.Plater, L.Innes, A.Cowan, P.Jewsbury, and P.M.Fischer (2006).
REPLACE: a strategy for iterative design of cyclin-binding groove inhibitors.
  Chembiochem, 7, 1909-1915.
PDB codes: 2uue 2v22
17001081 N.Canela, M.Orzáez, R.Fucho, F.Mateo, R.Gutierrez, A.Pineda-Lucena, O.Bachs, and E.Pérez-Payá (2006).
Identification of an hexapeptide that binds to a surface pocket in cyclin A and inhibits the catalytic activity of the complex cyclin-dependent kinase 2-cyclin A.
  J Biol Chem, 281, 35942-35953.  
15123247 C.McInnes, S.Wang, S.Anderson, J.O'Boyle, W.Jackson, G.Kontopidis, C.Meades, M.Mezna, M.Thomas, G.Wood, D.P.Lane, and P.M.Fischer (2004).
Structural determinants of CDK4 inhibition and design of selective ATP competitive inhibitors.
  Chem Biol, 11, 525-534.  
15468065 G.M.Verkhivker (2004).
Protein conformational transitions coupled to binding in molecular recognition of unstructured proteins: hierarchy of structural loss from all-atom Monte Carlo simulations of p27Kip1 unfolding-unbinding and structural determinants of the binding mechanism.
  Biopolymers, 75, 420-433.  
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.