PDBsum entry 2v22

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protein ligands Protein-protein interface(s) links
Transferase PDB id
Protein chains
296 a.a. *
258 a.a. *
C35 ×2
Waters ×323
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Replace: a strategy for iterative design of cyclin binding groove inhibitors
Structure: Cell division protein kinase 2. Chain: a, c. Synonym: p33 protein kinase, cyclin-dependent kinase 2. 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. Expression_system_cell_line: sf9. Expressed in: escherichia coli. Expression_system_taxid: 562
2.60Å     R-factor:   0.174     R-free:   0.277
Authors: M.J.Andrews,G.Kontopidis,C.Mcinnes,A.Plater,L.Innes,A.Cowan, P.Jewsbury,P.M.Fischer
Key ref: M.J.Andrews et al. (2006). REPLACE: a strategy for iterative design of cyclin-binding groove inhibitors. Chembiochem, 7, 1909-1915. PubMed id: 17051658 DOI: 10.1002/cbic.200600189
31-May-07     Release date:   29-Jan-08    
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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   30 terms 
  Biochemical function     nucleotide binding     13 terms  


DOI no: 10.1002/cbic.200600189 Chembiochem 7:1909-1915 (2006)
PubMed id: 17051658  
REPLACE: a strategy for iterative design of cyclin-binding groove inhibitors.
M.J.Andrews, G.Kontopidis, C.McInnes, A.Plater, L.Innes, A.Cowan, P.Jewsbury, P.M.Fischer.
We describe a drug-design strategy termed REPLACE (REplacement with Partial Ligand Alternatives through Computational Enrichment) in which nonpeptidic surrogates for specific determinants of known peptide ligands are identified in silico by using a core peptide-bound protein structure as a design anchor. In the REPLACE application example, we present the effective replacement of two critical binding motifs in a lead protein-protein interaction inhibitor pentapeptide with more druglike phenyltriazole and diphenyl ether groups. These were identified through docking of fragment libraries into the volume of the cyclin-binding groove of CDK2/cyclin A vacated through truncation of the inhibitor peptide-binding determinants. Proof of concept for this strategy was obtained through the generation of potent peptide-small-molecule hybrids and by the confirmation of inhibitor-binding modes in X-ray crystal structures. This method therefore allows nonpeptide fragments to be identified without the requirement for a high-sensitivity binding assay and should be generally applicable in replacing amino acids as individual residues or groups in peptide inhibitors to generate pharmaceutically acceptable lead molecules.

Literature references that cite this PDB file's key reference

  PubMed id Reference
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
19568282 S.Lapenna, and A.Giordano (2009).
Cell cycle kinases as therapeutic targets for cancer.
  Nat Rev Drug Discov, 8, 547-566.  
18328830 J.Z.Zhou (2008).
Structure-directed combinatorial library design.
  Curr Opin Chem Biol, 12, 379-385.  
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.