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PDBsum entry 1gij

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Transferase PDB id
1gij
Jmol
Contents
Protein chain
273 a.a. *
Ligands
2PU
Waters ×76
* Residue conservation analysis
PDB id:
1gij
Name: Transferase
Title: Human cyclin dependent kinase 2 complexed with the cdk4 inhibitor
Structure: Cell division protein kinase 2. Chain: a. Synonym: cyclin dependent kinase 2. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
Resolution:
2.20Å     R-factor:   0.228     R-free:   0.286
Authors: M.Ikuta,S.Nishimura
Key ref:
M.Ikuta et al. (2001). Crystallographic approach to identification of cyclin-dependent kinase 4 (CDK4)-specific inhibitors by using CDK4 mimic CDK2 protein. J Biol Chem, 276, 27548-27554. PubMed id: 11335721 DOI: 10.1074/jbc.M102060200
Date:
06-Feb-01     Release date:   06-Feb-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
Seq:
Struc:
298 a.a.
273 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: 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   27 terms 
  Biochemical function     nucleotide binding     12 terms  

 

 
    reference    
 
 
DOI no: 10.1074/jbc.M102060200 J Biol Chem 276:27548-27554 (2001)
PubMed id: 11335721  
 
 
Crystallographic approach to identification of cyclin-dependent kinase 4 (CDK4)-specific inhibitors by using CDK4 mimic CDK2 protein.
M.Ikuta, K.Kamata, K.Fukasawa, T.Honma, T.Machida, H.Hirai, I.Suzuki-Takahashi, T.Hayama, S.Nishimura.
 
  ABSTRACT  
 
Genetic alteration of one or more components of the p16(INK4A)-CDK4,6/cyclin D-retinoblastoma pathway is found in more than half of all human cancers. Therefore, CDK4 is an attractive target for the development of a novel anticancer agent. However, it is difficult to make CDK4-specific inhibitors that do not possess activity for other kinases, especially CDK2, because the CDK family has high structural homology. The three-dimensional structure of CDK2, particularly that bound with the inhibitor, has provided useful information for the synthesis of CDK2-specific inhibitors. The same approach used to make CDK4-specific inhibitors was hindered by the failure to obtain a crystal structure of CDK4. To overcome this problem, we synthesized a CDK4 mimic CDK2 protein in which the ATP binding pocket of CDK2 was replaced with that of CDK4. This CDK4 mimic CDK2 was crystallized both in the free and inhibitor-bound form. The structural information thus obtained was found to be useful for synthesis of a CDK4-specific inhibitor that does not have substantial CDK2 activity. Namely, the data suggest that CDK4 has additional space that will accommodate a large substituent such as the CDK4 selective inhibitor. Inhibitors designed to bind into this large cavity should be selective for CDK4 without having substantial CDK2 activity. This design principle was confirmed in the x-ray crystal structure of the CDK4 mimic CDK2 with a new CDK4 selective inhibitor bound.
 
  Selected figure(s)  
 
Figure 2.
Fig. 2. The hydrogen bond and hydrophobic interactions of compound I bound to wild-type CDK2. Compound I is shown in magenta. Wild-type CDK2 is shown in green. The figure was prepared using InsightII (Molecular Simulations, Inc.).
Figure 5.
Fig. 5. The hydrogen bond and hydrophobic interactions of compound II bound to CDK4 mimic CDK2. Compound II is shown in magenta. CDK4 mimic CDK2 is shown in green.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2001, 276, 27548-27554) copyright 2001.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20003365 T.Liu, and R.B.Altman (2009).
Prediction of calcium-binding sites by combining loop-modeling with machine learning.
  BMC Struct Biol, 9, 72.  
18043801 T.Persson, C.W.Yde, J.E.Rasmussen, T.L.Rasmussen, B.Guerra, O.G.Issinger, and J.Nielsen (2007).
Pyrazole carboxamides and carboxylic acids as protein kinase inhibitors in aberrant eukaryotic signal transduction: induction of growth arrest in MCF-7 cancer cells.
  Org Biomol Chem, 5, 3963-3970.  
16584130 J.Sridhar, N.Akula, and N.Pattabiraman (2006).
Selectivity and potency of cyclin-dependent kinase inhibitors.
  AAPS J, 8, E204-E221.  
16611982 K.Terasawa, K.Yoshimatsu, S.Iemura, T.Natsume, K.Tanaka, and Y.Minami (2006).
Cdc37 interacts with the glycine-rich loop of Hsp90 client kinases.
  Mol Cell Biol, 26, 3378-3389.  
16845019 L.Martin, V.Catherinot, and G.Labesse (2006).
kinDOCK: a tool for comparative docking of protein kinase ligands.
  Nucleic Acids Res, 34, W325-W329.  
16892371 M.D.Kelly, and R.L.Mancera (2006).
Comparative analysis of the surface interaction properties of the binding sites of CDK2, CDK4, and ERK2.
  ChemMedChem, 1, 366-375.  
16075305 K.A.Rossi, J.A.Markwalder, S.P.Seitz, C.H.Chang, S.Cox, M.D.Boisclair, L.Brizuela, S.L.Brenner, and P.F.Stouten (2005).
Understanding and modulating cyclin-dependent kinase inhibitor specificity: molecular modeling and biochemical evaluation of pyrazolopyrimidinones as CDK2/cyclin A and CDK4/cyclin D1 inhibitors.
  J Comput Aided Mol Des, 19, 111-122.  
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.  
15505811 H.Park, M.S.Yeom, and S.Lee (2004).
Loop flexibility and solvent dynamics as determinants for the selective inhibition of cyclin-dependent kinase 4: comparative molecular dynamics simulation studies of CDK2 and CDK4.
  Chembiochem, 5, 1662-1672.  
15165511 M.Koresawa, and T.Okabe (2004).
High-throughput screening with quantitation of ATP consumption: a universal non-radioisotope, homogeneous assay for protein kinase.
  Assay Drug Dev Technol, 2, 153-160.  
12556199 N.C.Waters, and J.A.Geyer (2003).
Cyclin-dependent protein kinases as therapeutic drug targets for antimalarial drug development.
  Expert Opin Ther Targets, 7, 7.  
12789688 T.Honma (2003).
Recent advances in de novo design strategy for practical lead identification.
  Med Res Rev, 23, 606-632.  
12047871 G.Scapin (2002).
Structural biology in drug design: selective protein kinase inhibitors.
  Drug Discov Today, 7, 601-611.  
  12163365 M.L.Rodriguez-Puebla, P.L.Miliani de Marval, M.LaCava, D.S.Moons, H.Kiyokawa, and C.J.Conti (2002).
Cdk4 deficiency inhibits skin tumor development but does not affect normal keratinocyte proliferation.
  Am J Pathol, 161, 405-411.  
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.