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PDBsum entry 1e1x
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Protein kinase PDB id
1e1x

 

 

 

 

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JSmol PyMol  
Contents
Protein chain
291 a.a. *
Ligands
NW1
Waters ×143
* Residue conservation analysis
PDB id:
1e1x
Name: Protein kinase
Title: Human cyclin dependent kinase 2 complexed with the inhibitor nu6027
Structure: Cyclin-dependent protein kinase 2. Chain: a. Synonym: cdk2. Engineered: yes. Other_details: complex with cyclin a or cyclin e
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
Resolution:
1.85Å     R-factor:   0.213     R-free:   0.281
Authors: J.A.Endicott,M.E.M.Noble,L.N.Johnson
Key ref: C.E.Arris et al. (2000). Identification of novel purine and pyrimidine cyclin-dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles. J Med Chem, 43, 2797-2804. PubMed id: 10956187 DOI: 10.1021/jm990628o
Date:
11-May-00     Release date:   10-May-01    
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.
290 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/jm990628o J Med Chem 43:2797-2804 (2000)
PubMed id: 10956187  
 
 
Identification of novel purine and pyrimidine cyclin-dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles.
C.E.Arris, F.T.Boyle, A.H.Calvert, N.J.Curtin, J.A.Endicott, E.F.Garman, A.E.Gibson, B.T.Golding, S.Grant, R.J.Griffin, P.Jewsbury, L.N.Johnson, A.M.Lawrie, D.R.Newell, M.E.Noble, E.A.Sausville, R.Schultz, W.Yu.
 
  ABSTRACT  
 
Substituted guanines and pyrimidines were tested as inhibitors of cyclin B1/CDK1 and cyclin A3/CDK2 and soaked into crystals of monomeric CDK2. O6-Cyclohexylmethylguanine (NU2058) was a competitive inhibitor of CDK1 and CDK2 with respect to ATP (Ki values: CDK1, 5 +/- 1 microM; CDK2, 12 +/- 3 microM) and formed a triplet of hydrogen bonds (i.e., NH-9 to Glu 81, N-3 to Leu 83, and 2-NH2 to Leu 83). The triplet of hydrogen bonding and CDK inhibition was reproduced by 2,6-diamino-4-cyclohexylmethyloxy-5-nitrosopyrimidine (NU6027, Ki values: CDK1, 2.5 +/- 0.4 microM; CDK2, 1.3 +/- 0.2 microM). Against human tumor cells, NU2058 and NU6027 were growth inhibitory in vitro (mean GI50 values of 13 +/- 7 microM and 10 +/- 6 microM, respectively), with a pattern of sensitivity distinct from flavopiridol and olomoucine. These CDK inhibition and chemosensitivity data indicate that the distinct mode of binding of NU2058 and NU6027 has direct consequences for enzyme and cell growth inhibition.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21734724 E.A.Musgrove, C.E.Caldon, J.Barraclough, A.Stone, and R.L.Sutherland (2011).
Cyclin D as a therapeutic target in cancer.
  Nat Rev Cancer, 11, 558-572.  
21240418 M.A.Galindo, J.Hannant, R.W.Harrington, W.Clegg, B.R.Horrocks, A.R.Pike, and A.Houlton (2011).
Pyrrolyl-, 2-(2-thienyl)pyrrolyl- and 2,5-bis(2-thienyl)pyrrolyl-nucleosides: synthesis, molecular and electronic structure, and redox behaviour of C5-thymidine derivatives.
  Org Biomol Chem, 9, 1555-1564.  
21286784 P.Dobeš, J.Fanfrlík, J.Rezáč, M.Otyepka, and P.Hobza (2011).
Transferable scoring function based on semiempirical quantum mechanical PM6-DH2 method: CDK2 with 15 structurally diverse inhibitors.
  J Comput Aided Mol Des, 25, 223-235.  
20448906 C.Wong, R.J.Griffin, I.R.Hardcastle, J.S.Northen, L.Z.Wang, and B.T.Golding (2010).
Synthesis of sulfonamide-based kinase inhibitors from sulfonates by exploiting the abrogated SN2 reactivity of 2,2,2-trifluoroethoxysulfonates.
  Org Biomol Chem, 8, 2457-2464.  
20448898 F.Marchetti, C.Cano, N.J.Curtin, B.T.Golding, R.J.Griffin, K.Haggerty, D.R.Newell, R.J.Parsons, S.L.Payne, L.Z.Wang, and I.R.Hardcastle (2010).
Synthesis and biological evaluation of 5-substituted O4-alkylpyrimidines as CDK2 inhibitors.
  Org Biomol Chem, 8, 2397-2407.  
  20054100 J.Holcakova, P.Tomasec, J.J.Bugert, E.C.Wang, G.W.Wilkinson, R.Hrstka, V.Krystof, M.Strnad, and B.Vojtesek (2010).
The inhibitor of cyclin-dependent kinases, olomoucine II, exhibits potent antiviral properties.
  Antivir Chem Chemother, 20, 133-142.  
20010939 N.Johnson, J.Bentley, L.Z.Wang, D.R.Newell, C.N.Robson, G.I.Shapiro, and N.J.Curtin (2010).
Pre-clinical evaluation of cyclin-dependent kinase 2 and 1 inhibition in anti-estrogen-sensitive and resistant breast cancer cells.
  Br J Cancer, 102, 342-350.  
20919954 Y.Jiang, S.Zhou, G.E.Sandusky, M.R.Kelley, and M.L.Fishel (2010).
Reduced expression of DNA repair and redox signaling protein APE1/Ref-1 impairs human pancreatic cancer cell survival, proliferation, and cell cycle progression.
  Cancer Invest, 28, 885-895.  
19415659 D.Raffa, B.Maggio, S.Cascioferro, M.V.Raimondi, G.Daidone, S.Plescia, D.Schillaci, M.G.Cusimano, L.Titone, C.Colomba, and M.Tolomeo (2009).
N-(indazolyl)benzamido derivatives as CDK1 inhibitors: design, synthesis, biological activity, and molecular docking studies.
  Arch Pharm (Weinheim), 342, 265-273.  
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.  
18941902 R.Gil-Redondo, J.Estrada, A.Morreale, F.Herranz, J.Sancho, and A.R.Ortiz (2009).
VSDMIP: virtual screening data management on an integrated platform.
  J Comput Aided Mol Des, 23, 171-184.  
17937404 T.O.Fischmann, A.Hruza, J.S.Duca, L.Ramanathan, T.Mayhood, W.T.Windsor, H.V.Le, T.J.Guzi, M.P.Dwyer, K.Paruch, R.J.Doll, E.Lees, D.Parry, W.Seghezzi, and V.Madison (2008).
Structure-guided discovery of cyclin-dependent kinase inhibitors.
  Biopolymers, 89, 372-379.
PDB codes: 2r3f 2r3g 2r3h 2r3i 2r3j 2r3k 2r3l 2r3m 2r3n 2r3o 2r3p 2r3q 2r3r
17599054 A.C.Rigas, C.N.Robson, and N.J.Curtin (2007).
Therapeutic potential of CDK inhibitor NU2058 in androgen-independent prostate cancer.
  Oncogene, 26, 7611-7619.  
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.  
17571187 F.Marchetti, K.L.Sayle, J.Bentley, W.Clegg, N.J.Curtin, J.A.Endicott, B.T.Golding, R.J.Griffin, K.Haggerty, R.W.Harrington, V.Mesguiche, D.R.Newell, M.E.Noble, R.J.Parsons, D.J.Pratt, L.Z.Wang, and I.R.Hardcastle (2007).
Structure-based design of 2-arylamino-4-cyclohexylmethoxy-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinase 2.
  Org Biomol Chem, 5, 1577-1585.  
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.  
17436259 K.Stierand, and M.Rarey (2007).
From Modeling to Medicinal Chemistry: Automatic Generation of Two-Dimensional Complex Diagrams.
  ChemMedChem, 2, 853-860.  
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.  
17123821 Y.M.Ahn, L.Vogeti, C.J.Liu, H.K.Santhapuram, J.M.White, V.Vasandani, L.A.Mitscher, G.H.Lushington, P.R.Hanson, D.R.Powell, R.H.Himes, K.F.Roby, Q.Ye, and G.I.Georg (2007).
Design, synthesis, and antiproliferative and CDK2-cyclin a inhibitory activity of novel flavopiridol analogues.
  Bioorg Med Chem, 15, 702-713.  
16698182 C.A.Rabik, M.C.Njoku, and M.E.Dolan (2006).
Inactivation of O6-alkylguanine DNA alkyltransferase as a means to enhance chemotherapy.
  Cancer Treat Rev, 32, 261-276.  
16374872 J.Bonet, G.Caltabiano, A.K.Khan, M.A.Johnston, C.Corbí, A.Gómez, X.Rovira, J.Teyra, and J.Villà-Freixa (2006).
The role of residue stability in transient protein-protein interactions involved in enzymatic phosphate hydrolysis. A computational study.
  Proteins, 63, 65-77.  
16584130 J.Sridhar, N.Akula, and N.Pattabiraman (2006).
Selectivity and potency of cyclin-dependent kinase inhibitors.
  AAPS J, 8, E204-E221.  
16802081 M.P.González, J.Caballero, A.M.Helguera, M.Garriga, G.González, and M.Fernández (2006).
2D autocorrelation modelling of the inhibitory activity of cytokinin-derived cyclin-dependent kinase inhibitors.
  Bull Math Biol, 68, 735-751.  
15993080 L.Havlicek, K.Fuksova, V.Krystof, M.Orsag, B.Vojtesek, and M.Strnad (2005).
8-Azapurines as new inhibitors of cyclin-dependent kinases.
  Bioorg Med Chem, 13, 5399-5407.  
15742385 O.Prien (2005).
Target-family-oriented focused libraries for kinases--conceptual design aspects and commercial availability.
  Chembiochem, 6, 500-505.  
15326593 A.M.Aronov, and G.W.Bemis (2004).
A minimalist approach to fragment-based ligand design using common rings and linkers: application to kinase inhibitors.
  Proteins, 57, 36-50.  
15003245 C.Luo, and P.Laaja (2004).
Inhibitors of JAKs/STATs and the kinases: a possible new cluster of drugs.
  Drug Discov Today, 9, 268-275.  
12557224 J.J.Molenaar, P.van Sluis, K.Boon, R.Versteeg, and H.N.Caron (2003).
Rearrangements and increased expression of cyclin D1 (CCND1) in neuroblastoma.
  Genes Chromosomes Cancer, 36, 242-249.  
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.  
11927285 E.A.Sausville (2002).
Complexities in the development of cyclin-dependent kinase inhibitor drugs.
  Trends Mol Med, 8, S32-S37.  
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.  
12237154 M.Knockaert, P.Greengard, and L.Meijer (2002).
Pharmacological inhibitors of cyclin-dependent kinases.
  Trends Pharmacol Sci, 23, 417-425.  
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
11746695 A.Cavalli, C.Dezi, G.Folkers, L.Scapozza, and M.Recanatini (2001).
Three-dimensional model of the cyclin-dependent kinase 1 (CDK1): Ab initio active site parameters for molecular dynamics studies of CDKS.
  Proteins, 45, 478-485.  
11673689 D.Sampath, and W.Plunkett (2001).
Design of new anticancer therapies targeting cell cycle checkpoint pathways.
  Curr Opin Oncol, 13, 484-490.  
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.

 

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