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PDBsum entry 1urc

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protein ligands Protein-protein interface(s) links
Transferase/inhibitor PDB id
1urc
Jmol
Contents
Protein chains
296 a.a. *
258 a.a. *
Ligands
ACE-ARG-LYS-LEU-
PHE-GLY
×2
Waters ×338
* Residue conservation analysis
PDB id:
1urc
Name: Transferase/inhibitor
Title: Cyclin a binding groove inhibitor ace-arg-lys-leu-phe-gly
Structure: Cell division protein kinase 2. Chain: a, c. Synonym: p33 protein kinase, cdk2, cyclin-dependent kinase- engineered: yes. Cyclin a2. Chain: b, d. Fragment: residues 173 - 432. Synonym: cyclin a, ccna2, ccna, ccn1. 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. Other_details: cyclin groove-bound cyclic(2-5) pentapeptide
Biol. unit: Trimer (from PDB file)
Resolution:
2.60Å     R-factor:   0.177     R-free:   0.254
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: M.J.Andrews et al. (2004). Design, synthesis, biological activity and structural analysis of cyclic peptide inhibitors targeting the substrate recruitment site of cyclin-dependent kinase complexes. Org Biomol Chem, 2, 2735-2741. PubMed id: 15455144 DOI: 10.1039/B409157D
Date:
28-Oct-03     Release date:   31-Oct-03    
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: 10.1039/B409157D Org Biomol Chem 2:2735-2741 (2004)
PubMed id: 15455144  
 
 
Design, synthesis, biological activity and structural analysis of cyclic peptide inhibitors targeting the substrate recruitment site of cyclin-dependent kinase complexes.
M.J.Andrews, C.McInnes, G.Kontopidis, L.Innes, A.Cowan, A.Plater, P.M.Fischer.
 
  ABSTRACT  
 
Inhibition of cyclin A- and cyclin E-associated cyclin-dependent kinase-2 (CDK2) activities is an effective way of selective induction of apoptotic cell death via the E2F pathway in tumour cells. The cyclin groove recognition motif (CRM) in the natural CDK-inhibitory (CDKI) tumour suppressor protein p27KIP1 was used as the basis for the design and synthesis of a series of cyclic peptides whose biological activity and structural characterisation by NMR and X-ray crystallography is reported. Whereas linear p27KIP1 sequence peptides were comparatively ineffective, introduction of side chain-to-tail constraints was found to be productive. An optimal macrocyclic ring size for the conformational constraint was determined, mimicking the intramolecular H-bonding system of p27. Molecular dynamics calculations of various macrocycles suggested a close correlation between ring flexibility and biological activity. Truncated inhibitor peptide analogues also confirmed the hypothesis that introduction of a cyclic conformational constraint is favourable in terms of affinity and potency. The structural basis for the potency increase in cyclic versus linear peptides was demonstrated through the determination and interpretation of X-ray crystal structures of complexes between CDK2/cylin A (CDK2A) and a constrained pentapeptide.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20213667 V.Giménez-Oya, O.Villacañas, C.Obiol-Pardo, M.Antolin-Llovera, J.Rubio-Martinez, and S.Imperial (2011).
Design of novel ligands of CDP-methylerythritol kinase by mimicking direct protein-protein and solvent-mediated interactions.
  J Mol Recognit, 24, 71-80.  
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
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.  
19710018 P.Corsino, N.Horenstein, D.Ostrov, T.Rowe, M.Law, A.Barrett, G.Aslanidi, W.D.Cress, and B.Law (2009).
A novel class of cyclin-dependent kinase inhibitors identified by molecular docking act through a unique mechanism.
  J Biol Chem, 284, 29945-29955.  
17043661 L.Bagella, A.Sun, T.Tonini, G.Abbadessa, G.Cottone, M.G.Paggi, A.De Luca, P.P.Claudio, and A.Giordano (2007).
A small molecule based on the pRb2/p130 spacer domain leads to inhibition of cdk2 activity, cell cycle arrest and tumor growth reduction in vivo.
  Oncogene, 26, 1829-1839.  
16584130 J.Sridhar, N.Akula, and N.Pattabiraman (2006).
Selectivity and potency of cyclin-dependent kinase inhibitors.
  AAPS J, 8, E204-E221.  
16707497 K.Y.Cheng, M.E.Noble, V.Skamnaki, N.R.Brown, E.D.Lowe, L.Kontogiannis, K.Shen, P.A.Cole, G.Siligardi, and L.N.Johnson (2006).
The role of the phospho-CDK2/cyclin A recruitment site in substrate recognition.
  J Biol Chem, 281, 23167-23179.
PDB codes: 2cch 2cci
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.  
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.