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PDBsum entry 1h26

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protein ligands Protein-protein interface(s) links
Cell cycle PDB id
1h26
Jmol
Contents
Protein chains
298 a.a. *
258 a.a. *
269 a.a. *
Ligands
SER-ARG-HIS-LYS-
LYS-LEU-MET-PHE-
LYS
Waters ×193
* Residue conservation analysis
PDB id:
1h26
Name: Cell cycle
Title: Cdk2/cyclin a in complex with an 11-residue recruitment peptide from p53
Structure: Cell division protein kinase 2. Chain: a, c. Synonym: cyclin-dependent kinase 2, p33 protein kinase. Engineered: yes. Other_details: phosphorylated on thr160. Cyclin a2. Chain: b, d. Fragment: cyclin fold, residues 175-432. Synonym: cyclin a.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Organism_taxid: 9606
Biol. unit: Dimer (from PDB file)
Resolution:
2.24Å     R-factor:   0.219     R-free:   0.268
Authors: I.Tews,K.Y.Cheng,E.D.Lowe,M.E.M.Noble,N.R.Brown,S.Gul, S.Gamblin,L.N.Johnson
Key ref:
E.D.Lowe et al. (2002). Specificity determinants of recruitment peptides bound to phospho-CDK2/cyclin A. Biochemistry, 41, 15625-15634. PubMed id: 12501191 DOI: 10.1021/bi0268910
Date:
31-Jul-02     Release date:   01-Feb-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
Seq:
Struc:
298 a.a.
298 a.a.*
Protein chains
Pfam   ArchSchema ?
P20248  (CCNA2_HUMAN) -  Cyclin-A2
Seq:
Struc:
432 a.a.
258 a.a.
Protein chain
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
Seq:
Struc:
298 a.a.
269 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 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: 10.1021/bi0268910 Biochemistry 41:15625-15634 (2002)
PubMed id: 12501191  
 
 
Specificity determinants of recruitment peptides bound to phospho-CDK2/cyclin A.
E.D.Lowe, I.Tews, K.Y.Cheng, N.R.Brown, S.Gul, M.E.Noble, S.J.Gamblin, L.N.Johnson.
 
  ABSTRACT  
 
Progression through S phase of the eukaryotic cell cycle is regulated by the action of the cyclin dependent protein kinase 2 (CDK2) in association with cyclin A. CDK2/cyclin A phosphorylates numerous substrates. Substrate specificity often employs a dual recognition strategy in which the sequence flanking the phospho-acceptor site (Ser.Pro.X.Arg/Lys) is recognized by CDK2, while the cyclin A component of the complex contains a hydrophobic site that binds Arg/Lys.X.Leu ("RXL" or "KXL") substrate recruitment motifs. To determine additional sequence specificity motifs around the RXL sequence, we have performed X-ray crystallographic studies at 2.3 A resolution and isothermal calorimetry measurements on complexes of phospho-CDK2/cyclin A with a recruitment peptide derived from E2F1 and with shorter 11-mer peptides from p53, pRb, p27, E2F1, and p107. The results show that the cyclin recruitment site accommodates a second hydrophobic residue either immediately C-terminal or next adjacent to the leucine of the "RXL" motif and that this site makes important contributions to the recruitment peptide recognition. The arginine of the RXL motif contacts a glutamate, Glu220, on the cyclin. In those substrates that contain a KXL motif, no ionic interactions are observed with the lysine. The sequences N-terminal to the "RXL" motif of the individual peptides show no conservation, but nevertheless make common contacts to the cyclin through main chain interactions. Thus, the recruitment site is able to recognize diverse but conformationally constrained target sequences. The observations have implications for the further identification of physiological substrates of CDK2/cyclin A and the design of specific inhibitors.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21071205 G.Schreiber, and A.E.Keating (2011).
Protein binding specificity versus promiscuity.
  Curr Opin Struct Biol, 21, 50-61.  
21181781 J.Y.Yoo, S.H.Hwang, Y.S.Han, and S.Cho (2011).
Isolation and expression analysis of a homolog of the 14-3-3 epsilon gene in the diamondback moth, Plutella xylostella.
  Arch Insect Biochem Physiol, 76, 114-124.  
  20516128 A.C.Joerger, and A.R.Fersht (2010).
The tumor suppressor p53: from structures to drug discovery.
  Cold Spring Harb Perspect Biol, 2, a000919.  
20694007 A.Hirschi, M.Cecchini, R.C.Steinhardt, M.R.Schamber, F.A.Dick, and S.M.Rubin (2010).
An overlapping kinase and phosphatase docking site regulates activity of the retinoblastoma protein.
  Nat Struct Mol Biol, 17, 1051-1057.
PDB code: 3n5u
21152297 B.Xue, A.K.Dunker, and V.N.Uversky (2010).
Retro-MoRFs: Identifying Protein Binding Sites by Normal and Reverse Alignment and Intrinsic Disorder Prediction.
  Int J Mol Sci, 11, 3725-3747.  
20100603 B.Xue, R.L.Dunbrack, R.W.Williams, A.K.Dunker, and V.N.Uversky (2010).
PONDR-FIT: a meta-predictor of intrinsically disordered amino acids.
  Biochim Biophys Acta, 1804, 996.  
20133761 G.Pascreau, F.Eckerdt, M.E.Churchill, and J.L.Maller (2010).
Discovery of a distinct domain in cyclin A sufficient for centrosomal localization independently of Cdk binding.
  Proc Natl Acad Sci U S A, 107, 2932-2937.  
20215406 N.A.Copeland, H.E.Sercombe, J.F.Ainscough, and D.Coverley (2010).
Ciz1 cooperates with cyclin-A-CDK2 to activate mammalian DNA replication in vitro.
  J Cell Sci, 123, 1108-1115.  
19852836 A.Via, C.M.Gould, C.Gemünd, T.J.Gibson, and M.Helmer-Citterich (2009).
A structure filter for the Eukaryotic Linear Motif Resource.
  BMC Bioinformatics, 10, 351.  
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.  
19763085 S.Tyagi, and W.Herr (2009).
E2F1 mediates DNA damage and apoptosis through HCF-1 and the MLL family of histone methyltransferases.
  EMBO J, 28, 3185-3195.  
19845408 Z.Huang, and C.F.Wong (2009).
Docking flexible peptide to flexible protein by molecular dynamics using two implicit-solvent models: an evaluation in protein kinase and phosphatase systems.
  J Phys Chem B, 113, 14343-14354.  
18410249 A.C.Joerger, and A.R.Fersht (2008).
Structural biology of the tumor suppressor p53.
  Annu Rev Biochem, 77, 557-582.  
18366598 C.J.Oldfield, J.Meng, J.Y.Yang, M.Q.Yang, V.N.Uversky, and A.K.Dunker (2008).
Flexible nets: disorder and induced fit in the associations of p53 and 14-3-3 with their partners.
  BMC Genomics, 9, S1.  
18619997 M.S.Cortese, V.N.Uversky, and A.K.Dunker (2008).
Intrinsic disorder in scaffold proteins: getting more from less.
  Prog Biophys Mol Biol, 98, 85.  
17373709 G.Lolli, and L.N.Johnson (2007).
Recognition of Cdk2 by Cdk7.
  Proteins, 67, 1048-1059.
PDB code: 2hic
17431409 P.GawliƄski, R.Nikolay, C.Goursot, S.Lawo, B.Chaurasia, H.M.Herz, Y.Kussler-Schneider, T.Ruppert, M.Mayer, and J.Grosshans (2007).
The Drosophila mitotic inhibitor Frühstart specifically binds to the hydrophobic patch of cyclins.
  EMBO Rep, 8, 490-496.  
17612494 S.Tyagi, A.L.Chabes, J.Wysocka, and W.Herr (2007).
E2F activation of S phase promoters via association with HCF-1 and the MLL family of histone H3K4 methyltransferases.
  Mol Cell, 27, 107-119.  
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
16407256 M.Otyepka, I.Bártová, Z.Kríz, and J.Koca (2006).
Different mechanisms of CDK5 and CDK2 activation as revealed by CDK5/p25 and CDK2/cyclin A dynamics.
  J Biol Chem, 281, 7271-7281.  
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.  
16756506 R.P.Bhattacharyya, A.Reményi, B.J.Yeh, and W.A.Lim (2006).
Domains, motifs, and scaffolds: the role of modular interactions in the evolution and wiring of cell signaling circuits.
  Annu Rev Biochem, 75, 655-680.  
15649889 C.Gondeau, S.Gerbal-Chaloin, P.Bello, G.Aldrian-Herrada, M.C.Morris, and G.Divita (2005).
Design of a novel class of peptide inhibitors of cyclin-dependent kinase/cyclin activation.
  J Biol Chem, 280, 13793-13800.  
15660127 R.Honda, E.D.Lowe, E.Dubinina, V.Skamnaki, A.Cook, N.R.Brown, and L.N.Johnson (2005).
The structure of cyclin E1/CDK2: implications for CDK2 activation and CDK2-independent roles.
  EMBO J, 24, 452-463.
PDB code: 1w98
15701793 T.Gildor, R.Shemer, A.Atir-Lande, and D.Kornitzer (2005).
Coevolution of cyclin Pcl5 and its substrate Gcn4.
  Eukaryot Cell, 4, 310-318.  
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.  
15343278 N.J.Dibb, S.M.Dilworth, and C.D.Mol (2004).
Switching on kinases: oncogenic activation of BRAF and the PDGFR family.
  Nat Rev Cancer, 4, 718-727.  
15273306 N.Kannan, and A.F.Neuwald (2004).
Evolutionary constraints associated with functional specificity of the CMGC protein kinases MAPK, CDK, GSK, SRPK, DYRK, and CK2alpha.
  Protein Sci, 13, 2059-2077.  
12869192 E.De Moliner, N.R.Brown, and L.N.Johnson (2003).
Alternative binding modes of an inhibitor to two different kinases.
  Eur J Biochem, 270, 3174-3181.
PDB code: 1p5e
14592974 K.Y.Cheng, E.D.Lowe, J.Sinclair, E.A.Nigg, and L.N.Johnson (2003).
The crystal structure of the human polo-like kinase-1 polo box domain and its phospho-peptide complex.
  EMBO J, 22, 5757-5768.
PDB codes: 1q4k 1q4o
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 code is shown on the right.