spacer
spacer

PDBsum entry 1hcl
Go to PDB code: 
protein links
Protein kinase PDB id
1hcl

 

 

 

 

Loading ...

 
JSmol PyMol  
Contents
Protein chain
294 a.a. *
Waters ×180
* Residue conservation analysis
PDB id:
1hcl
Name: Protein kinase
Title: Human cyclin-dependent kinase 2
Structure: Human cyclin-dependent kinase 2. Chain: a. Synonym: cdk2. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Cell_line: sf9. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Resolution:
1.80Å     R-factor:   0.181     R-free:   0.254
Authors: U.Schulze-Gahmen,H.L.De Bondt,S.-H.Kim
Key ref: U.Schulze-Gahmen et al. (1996). High-resolution crystal structures of human cyclin-dependent kinase 2 with and without ATP: bound waters and natural ligand as guides for inhibitor design. J Med Chem, 39, 4540-4546. PubMed id: 8917641 DOI: 10.1021/jm960402a
Date:
03-Jun-96     Release date:   07-Dec-96    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2 from Homo sapiens
Seq:
Struc: 		298 a.a.
294 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.7.11.22  - cyclin-dependent kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction:
1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
L-seryl-[protein]
 + ATP
 = O-phospho-L-seryl-[protein]
 + ADP
 + H(+)
L-threonyl-[protein]
 + ATP
 = O-phospho-L-threonyl-[protein]
 + ADP
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1021/jm960402a J Med Chem 39:4540-4546 (1996)
PubMed id: 8917641  
 
 
High-resolution crystal structures of human cyclin-dependent kinase 2 with and without ATP: bound waters and natural ligand as guides for inhibitor design.
U.Schulze-Gahmen, H.L.De Bondt, S.H.Kim.
 
  ABSTRACT  
 
Inhibition of the cell cycle is widely considered as a new approach toward treatment for diseases caused by unregulated cell proliferation, including cancer. Since cyclin-dependent kinases (CDKs) are key enzymes of cell cycle control, they are promissing targets for the design and discovery of drugs with antiproliferative activity. The detailed structural analysis of CDK2 can provide valuable information for the design of new ligands that can bind in the ATP binding pocket and inhibit CDK2 activity. For this objective, the crystal structures of human CDK2 apoenzyme and its ATP complex were refined to 1.8 and 1.9 A, respectively. The high-resolution refinement reveals 12 ordered water molecules in the ATP binding pocket of the apoenzyme and five ordered waters in that of the ATP complex. Despite a large number of hydrogen bonds between ATP-phosphates and CDK2, binding studies of cyclic AMP-dependent protein kinase with ATP analogues show that the triphosphate moiety contributes little and the adenine ring is most important for binding affinity. Our analysis of CDK2 structural data, hydration of residues in the binding pocket of the apoenzyme, flexibility of the ligand, and structural differences between the apoenzyme and CDK2-ATP complex provide an explanation for the results of earlier binding studies with ATP analogues and a basis for future inhibitor design.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20336692 M.Rabiller, M.Getlik, S.Klüter, A.Richters, S.Tückmantel, J.R.Simard, and D.Rauh (2010).
Proteus in the world of proteins: conformational changes in protein kinases.
  Arch Pharm (Weinheim), 343, 193-206.  
19114556 A.Gárriz, H.Qiu, M.Dey, E.J.Seo, T.E.Dever, and A.G.Hinnebusch (2009).
A network of hydrophobic residues impeding helix alphaC rotation maintains latency of kinase Gcn2, which phosphorylates the alpha subunit of translation initiation factor 2.
  Mol Cell Biol, 29, 1592-1607.  
19361221 A.G.Turjanski, G.Hummer, and J.S.Gutkind (2009).
How mitogen-activated protein kinases recognize and phosphorylate their targets: A QM/MM study.
  J Am Chem Soc, 131, 6141-6148.  
19566963 B.T.Tobe, A.A.Kitazono, J.S.Garcia, R.A.Gerber, B.J.Bevis, J.S.Choy, D.Chasman, and S.J.Kron (2009).
Morphogenesis signaling components influence cell cycle regulation by cyclin dependent kinase.
  Cell Div, 4, 12.  
19513107 E.Zeqiraj, B.M.Filippi, S.Goldie, I.Navratilova, J.Boudeau, M.Deak, D.R.Alessi, and D.M.van Aalten (2009).
ATP and MO25alpha regulate the conformational state of the STRADalpha pseudokinase and activation of the LKB1 tumour suppressor.
  PLoS Biol, 7, e1000126.
PDB code: 3gni
18704950 K.O.Wrzeszczynski, and B.Rost (2009).
Cell cycle kinases predicted from conserved biophysical properties.
  Proteins, 74, 655-668.  
19437469 L.M.Elphick, S.E.Lee, E.S.Child, A.Prasad, C.Pignocchi, S.Thibaudeau, A.A.Anderson, L.Bonnac, V.Gouverneur, and D.J.Mann (2009).
A quantitative comparison of wild-type and gatekeeper mutant cdk2 for chemical genetic studies with ATP analogues.
  Chembiochem, 10, 1519-1526.  
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.  
17286863 J.Gu, and P.E.Bourne (2007).
Identifying allosteric fluctuation transitions between different protein conformational states as applied to Cyclin Dependent Kinase 2.
  BMC Bioinformatics, 8, 45.  
16374623 A.T.García-Sosa, and R.L.Mancera (2006).
The effect of a tightly bound water molecule on scaffold diversity in the computer-aided de novo ligand design of CDK2 inhibitors.
  J Mol Model, 12, 422-431.  
16493461 C.Aubry, A.J.Wilson, P.R.Jenkins, S.Mahale, B.Chaudhuri, J.D.Maréchal, and M.J.Sutcliffe (2006).
Design, synthesis and biological activity of new CDK4-specific inhibitors, based on fascaplysin.
  Org Biomol Chem, 4, 787-801.  
16584130 J.Sridhar, N.Akula, and N.Pattabiraman (2006).
Selectivity and potency of cyclin-dependent kinase inhibitors.
  AAPS J, 8, E204-E221.  
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.  
16244704 E.D.Scheeff, and P.E.Bourne (2005).
Structural evolution of the protein kinase-like superfamily.
  PLoS Comput Biol, 1, e49.  
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
11807175 I.R.Hardcastle, B.T.Golding, and R.J.Griffin (2002).
Designing inhibitors of cyclin-dependent kinases.
  Annu Rev Pharmacol Toxicol, 42, 325-348.  
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.  
11306297 A.C.Bishop, O.Buzko, and K.M.Shokat (2001).
Magic bullets for protein kinases.
  Trends Cell Biol, 11, 167-172.  
11354366 T.M.Sielecki, T.L.Johnson, J.Liu, J.K.Muckelbauer, R.H.Grafstrom, S.Cox, J.Boylan, C.R.Burton, H.Chen, A.Smallwood, C.H.Chang, M.Boisclair, P.A.Benfield, G.L.Trainor, and S.P.Seitz (2001).
Quinazolines as cyclin dependent kinase inhibitors.
  Bioorg Med Chem Lett, 11, 1157-1160.
PDB code: 2b53
10608920 C.García-Echeverría, P.Traxler, and D.B.Evans (2000).
ATP site-directed competitive and irreversible inhibitors of protein kinases.
  Med Res Rev, 20, 28-57.  
10713991 K.A.Denessiouk, and M.S.Johnson (2000).
When fold is not important: a common structural framework for adenine and AMP binding in 12 unrelated protein families.
  Proteins, 38, 310-326.  
10662688 L.Meijer, A.M.Thunnissen, A.W.White, M.Garnier, M.Nikolic, L.H.Tsai, J.Walter, K.E.Cleverley, P.C.Salinas, Y.Z.Wu, J.Biernat, E.M.Mandelkow, S.H.Kim, and G.R.Pettit (2000).
Inhibition of cyclin-dependent kinases, GSK-3beta and CK1 by hymenialdisine, a marine sponge constituent.
  Chem Biol, 7, 51-63.
PDB code: 1dm2
10454204 M.E.Noble, and J.A.Endicott (1999).
Chemical inhibitors of cyclin-dependent kinases: insights into design from X-ray crystallographic studies.
  Pharmacol Ther, 82, 269-278.  
10029530 N.Narayana, T.C.Diller, K.Koide, M.E.Bunnage, K.C.Nicolaou, L.L.Brunton, N.H.Xuong, L.F.Ten Eyck, and S.S.Taylor (1999).
Crystal structure of the potent natural product inhibitor balanol in complex with the catalytic subunit of cAMP-dependent protein kinase.
  Biochemistry, 38, 2367-2376.
PDB code: 1bx6
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.

 

spacer
spacer