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PDBsum entry 1e9h

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protein ligands Protein-protein interface(s) links
Cell cycle PDB id
1e9h
Jmol
Contents
Protein chains
296 a.a. *
258 a.a. *
Ligands
INR ×2
Waters ×369
* Residue conservation analysis
PDB id:
1e9h
Name: Cell cycle
Title: Thr 160 phosphorylated cdk2 - human cyclin a3 complex with the inhibitor indirubin-5-sulphonate bound
Structure: Cell division protein kinase 2. Chain: a, c. Synonym: cyclin-dependent kinase 2, cdk2. Engineered: yes. Other_details: phosphorylated on thr 160 chains a and c are asymetric unit copies. Cyclin a3. Chain: b, d. Synonym: a3.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562
Biol. unit: Hetero-Dimer (from PDB file)
Resolution:
2.5Å     R-factor:   0.225     R-free:   0.273
Authors: T.G.Davies,P.Tunnah,M.E.M.Noble,J.A.Endicott
Key ref:
T.G.Davies et al. (2001). Inhibitor binding to active and inactive CDK2: the crystal structure of CDK2-cyclin A/indirubin-5-sulphonate. Structure, 9, 389-397. PubMed id: 11377199 DOI: 10.1016/S0969-2126(01)00598-6
Date:
16-Oct-00     Release date:   11-Oct-01    
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
* PDB and UniProt seqs differ at 1 residue position (black cross)

 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: 10.1016/S0969-2126(01)00598-6 Structure 9:389-397 (2001)
PubMed id: 11377199  
 
 
Inhibitor binding to active and inactive CDK2: the crystal structure of CDK2-cyclin A/indirubin-5-sulphonate.
T.G.Davies, P.Tunnah, L.Meijer, D.Marko, G.Eisenbrand, J.A.Endicott, M.E.Noble.
 
  ABSTRACT  
 
BACKGROUND: Cyclin-dependent kinase 2 (CDK2) is an important target for structure-based design of antitumor agents. Monomeric CDK2 is inactive. Activation requires rearrangements to key structural elements of the enzyme's active site, which accompany cyclin binding and phosphorylation. To assess the validity of using monomeric CDK2 as a model for the active kinase in structure-based drug design, we have solved the structure of the inhibitor indirubin-5-sulphonate (E226) complexed with phospho-CDK2-cyclin A and compared it with the structure of E226 bound to inactive, monomeric CDK2. RESULTS: Activation of monomeric CDK2 leads to a rotation of its N-terminal domain relative to the C-terminal lobe. The accompanying change in position of E226 follows that of the N-terminal domain, and its interactions with residues forming part of the adenine binding pocket are conserved. The environment of the ATP-ribose site, not explored by E226, is significantly different in the binary complex compared to the monomeric complex due to movement of the glycine loop. Conformational changes also result in subtle differences in hydrogen bonding and electrostatic interactions between E226's sulphonate and CDK2's phosphate binding site. Affinities calculated by LUDI for the interaction of E226 with active or inactive CDK2 differ by a factor of approximately ten. CONCLUSIONS: The accuracy of monomeric CDK2 as an inhibitor design template is restricted to the adenine binding site. The general flexibility observed for the glycine loop and subtle changes to the phosphate binding site suggest a need to study interactions between inhibitors and active CDK2 in structure-based drug design programs.
 
  Selected figure(s)  
 
Figure 7.
Figure 7. Stereo View Showing Superposition of Monomeric and Binary Structures, Showing Residues that Form Polar Contacts with the E226 Sulphonate GroupMonomeric and binary structures are colored in red and yellow, respectively. Hydrogen bonding and electrostatic interactions between the sulphonate group and active CDK2 are denoted by dashed lines

 
  The above figure is reprinted by permission from Cell Press: Structure (2001, 9, 389-397) copyright 2001.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21108279 G.Karapetyan, K.Chakrabarty, M.Hein, and P.Langer (2011).
Synthesis and bioactivity of carbohydrate derivatives of indigo, its isomers and heteroanalogues.
  ChemMedChem, 6, 25-37.  
21287607 J.M.Hayes, V.T.Skamnaki, G.Archontis, C.Lamprakis, J.Sarrou, N.Bischler, A.L.Skaltsounis, S.E.Zographos, and N.G.Oikonomakos (2011).
Kinetics, in silico docking, molecular dynamics, and MM-GBSA binding studies on prototype indirubins, KT5720, and staurosporine as phosphorylase kinase ATP-binding site inhibitors: The role of water molecules examined.
  Proteins, 79, 703-719.  
20237920 O.Sperandio, L.Mouawad, E.Pinto, B.O.Villoutreix, D.Perahia, and M.A.Miteva (2010).
How to choose relevant multiple receptor conformations for virtual screening: a test case of Cdk2 and normal mode analysis.
  Eur Biophys J, 39, 1365-1372.  
18183356 I.J.Enyedy, and W.J.Egan (2008).
Can we use docking and scoring for hit-to-lead optimization?
  J Comput Aided Mol Des, 22, 161-168.  
18816110 K.Vougogiannopoulou, Y.Ferandin, K.Bettayeb, V.Myrianthopoulos, O.Lozach, Y.Fan, C.H.Johnson, P.Magiatis, A.L.Skaltsounis, E.Mikros, and L.Meijer (2008).
Soluble 3',6-substituted indirubins with enhanced selectivity toward glycogen synthase kinase -3 alter circadian period.
  J Med Chem, 51, 6421-6431.  
16770643 B.Zhang, V.B.Tan, K.M.Lim, T.E.Tay, and S.Zhuang (2007).
Study of the inhibition of cyclin-dependent kinases with roscovitine and indirubin-3'-oxime from molecular dynamics simulations.
  J Mol Model, 13, 79-89.  
17085505 J.H.Alzate-Morales, R.Contreras, A.Soriano, I.Tuñon, and E.Silla (2007).
A computational study of the protein-ligand interactions in CDK2 inhibitors: using quantum mechanics/molecular mechanics interaction energy as a predictor of the biological activity.
  Biophys J, 92, 430-439.  
17541419 M.P.Mazanetz, and P.M.Fischer (2007).
Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases.
  Nat Rev Drug Discov, 6, 464-479.  
17533378 Y.Zhen, V.Sørensen, Y.Jin, Z.Suo, and A.WiedÅ‚ocha (2007).
Indirubin-3'-monoxime inhibits autophosphorylation of FGFR1 and stimulates ERK1/2 activity via p38 MAPK.
  Oncogene, 26, 6372-6385.  
  17172866 A.Duensing, L.Ghanem, R.A.Steinman, Y.Liu, and S.Duensing (2006).
p21(Waf1/Cip1) deficiency stimulates centriole overduplication.
  Cell Cycle, 5, 2899-2902.  
17054019 B.Zhang, V.B.Tan, K.M.Lim, and T.E.Tay (2006).
Molecular dynamics simulations on the inhibition of cyclin-dependent kinases 2 and 5 in the presence of activators.
  J Comput Aided Mol Des, 20, 395-404.  
16785236 G.Sethi, K.S.Ahn, S.K.Sandur, X.Lin, M.M.Chaturvedi, and B.B.Aggarwal (2006).
Indirubin enhances tumor necrosis factor-induced apoptosis through modulation of nuclear factor-kappa B signaling pathway.
  J Biol Chem, 281, 23425-23435.  
16702956 J.Ribas, K.Bettayeb, Y.Ferandin, M.Knockaert, X.Garrofé-Ochoa, F.Totzke, C.Schächtele, J.Mester, P.Polychronopoulos, P.Magiatis, A.L.Skaltsounis, J.Boix, and L.Meijer (2006).
7-Bromoindirubin-3'-oxime induces caspase-independent cell death.
  Oncogene, 25, 6304-6318.  
16584130 J.Sridhar, N.Akula, and N.Pattabiraman (2006).
Selectivity and potency of cyclin-dependent kinase inhibitors.
  AAPS J, 8, E204-E221.  
16765600 S.H.Kim, S.W.Kim, S.J.Choi, Y.C.Kim, and T.S.Kim (2006).
Enhancing effect of indirubin derivatives on 1,25-dihydroxyvitamin D3- and all-trans retinoic acid-induced differentiation of HL-60 leukemia cells.
  Bioorg Med Chem, 14, 6752-6758.  
16115123 K.Suzuki, R.Adachi, A.Hirayama, H.Watanabe, S.Otani, Y.Watanabe, and T.Kasahara (2005).
Indirubin, a Chinese anti-leukaemia drug, promotes neutrophilic differentiation of human myelocytic leukaemia HL-60 cells.
  Br J Haematol, 130, 681-690.  
15742375 R.Jautelat, T.Brumby, M.Schäfer, H.Briem, G.Eisenbrand, S.Schwahn, M.Krüger, U.Lücking, O.Prien, and G.Siemeister (2005).
From the insoluble dye indirubin towards highly active, soluble CDK2-inhibitors.
  Chembiochem, 6, 531-540.
PDB codes: 2bhe 2bhh
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.  
15153119 M.N.Kosmopoulou, D.D.Leonidas, E.D.Chrysina, N.Bischler, G.Eisenbrand, C.E.Sakarellos, R.Pauptit, and N.G.Oikonomakos (2004).
Binding of the potential antitumour agent indirubin-5-sulphonate at the inhibitor site of rabbit muscle glycogen phosphorylase b. Comparison with ligand binding to pCDK2-cyclin A complex.
  Eur J Biochem, 271, 2280-2290.
PDB code: 1uzu
15123286 Y.Wan, W.Hur, C.Y.Cho, Y.Liu, F.J.Adrian, O.Lozach, S.Bach, T.Mayer, D.Fabbro, L.Meijer, and N.S.Gray (2004).
Synthesis and target identification of hymenialdisine analogs.
  Chem Biol, 11, 247-259.  
14700633 L.Meijer, A.L.Skaltsounis, P.Magiatis, P.Polychronopoulos, M.Knockaert, M.Leost, X.P.Ryan, C.A.Vonica, A.Brivanlou, R.Dajani, C.Crovace, C.Tarricone, A.Musacchio, S.M.Roe, L.Pearl, and P.Greengard (2003).
GSK-3-selective inhibitors derived from Tyrian purple indirubins.
  Chem Biol, 10, 1255-1266.
PDB code: 1uv5
14700620 P.M.Fischer (2003).
CDK versus GSK-3 inhibition: a purple haze no longer?
  Chem Biol, 10, 1144-1146.  
12133723 P.L.Toogood (2002).
Progress toward the development of agents to modulate the cell cycle.
  Curr Opin Chem Biol, 6, 472-478.  
12191605 T.G.Davies, D.J.Pratt, J.A.Endicott, L.N.Johnson, and M.E.Noble (2002).
Structure-based design of cyclin-dependent kinase inhibitors.
  Pharmacol Ther, 93, 125-133.  
12244298 T.G.Davies, J.Bentley, C.E.Arris, F.T.Boyle, N.J.Curtin, J.A.Endicott, A.E.Gibson, B.T.Golding, R.J.Griffin, I.R.Hardcastle, P.Jewsbury, L.N.Johnson, V.Mesguiche, D.R.Newell, M.E.Noble, J.A.Tucker, L.Wang, and H.J.Whitfield (2002).
Structure-based design of a potent purine-based cyclin-dependent kinase inhibitor.
  Nat Struct Biol, 9, 745-749.
PDB codes: 1h1p 1h1q 1h1r 1h1s
12211034 W.M.Rockey, and A.H.Elcock (2002).
Progress toward virtual screening for drug side effects.
  Proteins, 48, 664-671.  
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.