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PDBsum entry 1h1s

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protein ligands Protein-protein interface(s) links
Transferase PDB id
1h1s
Jmol
Contents
Protein chains
297 a.a. *
258 a.a. *
Ligands
4SP ×2
Waters ×703
* Residue conservation analysis
PDB id:
1h1s
Name: Transferase
Title: Structure of human thr160-phospho cdk2/cyclin a complexed with the inhibitor nu6102
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. Synonym: cyclin a, cyclin a3. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562
Biol. unit: Dimer (from PDB file)
Resolution:
2.00Å     R-factor:   0.236     R-free:   0.286
Authors: T.G.Davies,M.E.M.Noble,J.A.Endicott,L.N.Johnson
Key ref:
T.G.Davies et al. (2002). Structure-based design of a potent purine-based cyclin-dependent kinase inhibitor. Nat Struct Biol, 9, 745-749. PubMed id: 12244298 DOI: 10.1038/nsb842
Date:
21-Jul-02     Release date:   19-Sep-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
Seq:
Struc:
298 a.a.
297 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: 10.1038/nsb842 Nat Struct Biol 9:745-749 (2002)
PubMed id: 12244298  
 
 
Structure-based design of a potent purine-based cyclin-dependent kinase inhibitor.
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, H.J.Whitfield.
 
  ABSTRACT  
 
Aberrant control of cyclin-dependent kinases (CDKs) is a central feature of the molecular pathology of cancer. Iterative structure-based design was used to optimize the ATP- competitive inhibition of CDK1 and CDK2 by O(6)-cyclohexylmethylguanines, resulting in O(6)-cyclohexylmethyl-2-(4'- sulfamoylanilino)purine. The new inhibitor is 1,000-fold more potent than the parent compound (K(i) values for CDK1 = 9 nM and CDK2 = 6 nM versus 5,000 nM and 12,000 nM, respectively, for O(6)-cyclohexylmethylguanine). The increased potency arises primarily from the formation of two additional hydrogen bonds between the inhibitor and Asp 86 of CDK2, which facilitate optimum hydrophobic packing of the anilino group with the specificity surface of CDK2. Cellular studies with O(6)-cyclohexylmethyl-2-(4'- sulfamoylanilino) purine demonstrated inhibition of MCF-7 cell growth and target protein phosphorylation, consistent with CDK1 and CDK2 inhibition. The work represents the first successful iterative synthesis of a potent CDK inhibitor based on the structure of fully activated CDK2-cyclin A. Furthermore, the potency of O(6)-cyclohexylmethyl-2-(4'- sulfamoylanilino)purine was both predicted and fully rationalized on the basis of protein-ligand interactions.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Inhibitor structures and binding of NU2058 to T160pCDK2 -cyclinA. a, Chemical structures of NU2058, NU6094, NU6086 and NU6102. b, T160pCDK2 -cyclinA -NU2058 structure. T160pCDK2 -cyclinA is drawn in ribbon representation. CDK2 is purple and cyclin A is gold. NU2058 bound in the CDK2 active site cleft is shown as a surface representation in green. c, CDK2 -NU2058 hydrogen bond interactions. Schematic representation of the conserved hydrogen bonds between backbone atoms of CDK2 residues Leu 83 and Glu 81, located in the hinge region, and NU2058. Hydrogen bonds are drawn as dotted lines. Arrows pointing towards Phe 80 and Lys 89 indicate the orientation of the inhibitor within the active site.
Figure 2.
Figure 2. Binding of NU6094, NU6086 and NU6102 to T160pCDK2 -cyclinA. a, T160pCDK2 -cyclinA -NU6094 structure. Selected CDK2 residues are drawn in ball-and-stick representation, with carbon atoms colored green (inhibitor) and yellow (CDK2). The final 2F[o]-F[c] electron density contoured at 0.24 e^- -3 for NU6094 is included. Hydrogen bonds in all panels except (b) are denoted by dashed lines. b, NU6094 bound to the CDK2 active site. NU6094 is depicted as yellow CPK spheres. The CDK2 molecular surface is colored by atom type: carbon, oxygen and nitrogen atoms are green, red and blue, respectively. The figure illustrates the complementarity of the NU6094 anilino ring to the shape of the hydrophobic tunnel leading to the specificity surface. c, T160pCDK2 -cyclinA -NU6086 structure. NU6086 and selected CDK2 residues are rendered in ball-and stick-representation, with carbon atoms colored as in (a). Both conformers of the anilino ring (denoted I and II) are included. The final 2F[o]-F[c] electron density for NU6086 is contoured at 0.24 e^- -3. d, T160pCDK2 -cyclinA -NU6102 structure. NU6102 and selected CDK2 residues are rendered in ball-and-stick representation, with carbon atoms colored as in (a). The final 2F[o]-F[c] electron density for NU6102 is contoured at 0.24 e^- -3. e, NU6102 bound to the CDK2 active site. The CDK2 molecular surface is rendered in transparent gray so that interactions between the NU6102 sulfonamide group and the backbone nitrogen and side chain oxygen of Asp 86 are visible. Hydrogen bonds are depicted by dotted lines. NU6102 is rendered in ball and stick, with carbon atoms colored green.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2002, 9, 745-749) copyright 2002.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
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.  
21070610 H.Wang, J.Blais, D.Ron, and T.Cardozo (2010).
Structural determinants of PERK inhibitor potency and selectivity.
  Chem Biol Drug Des, 76, 480-495.  
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.  
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.  
19816553 N.Okimoto, N.Futatsugi, H.Fuji, A.Suenaga, G.Morimoto, R.Yanai, Y.Ohno, T.Narumi, and M.Taiji (2009).
High-performance drug discovery: computational screening by combining docking and molecular dynamics simulations.
  PLoS Comput Biol, 5, e1000528.  
18230152 H.Chen, Q.Huang, J.Dong, D.Z.Zhai, A.D.Wang, and Q.Lan (2008).
Overexpression of CDC2/CyclinB1 in gliomas, and CDC2 depletion inhibits proliferation of human glioma cells in vitro and in vivo.
  BMC Cancer, 8, 29.  
18285371 I.M.Overton, G.Padovani, M.A.Girolami, and G.J.Barton (2008).
ParCrys: a Parzen window density estimation approach to protein crystallization propensity prediction.
  Bioinformatics, 24, 901-907.  
18256689 L.Krasinska, E.Besnard, E.Cot, C.Dohet, M.Méchali, J.M.Lemaitre, and D.Fisher (2008).
Cdk1 and Cdk2 activity levels determine the efficiency of replication origin firing in Xenopus.
  EMBO J, 27, 758-769.  
18421145 R.E.Hubbard (2008).
Fragment approaches in structure-based drug discovery.
  J Synchrotron Radiat, 15, 227-230.  
19104043 T.Hirota, W.G.Lewis, A.C.Liu, J.W.Lee, P.G.Schultz, and S.A.Kay (2008).
A chemical biology approach reveals period shortening of the mammalian circadian clock by specific inhibition of GSK-3beta.
  Proc Natl Acad Sci U S A, 105, 20746-20751.  
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.  
16680785 D.Dirnberger, G.Unsin, S.Schlenker, and C.Reichel (2006).
A small-molecule-protein interaction system with split-ubiquitin as sensor.
  Chembiochem, 7, 936-942.  
16988956 H.Park, J.Lee, and S.Lee (2006).
Critical assessment of the automated AutoDock as a new docking tool for virtual screening.
  Proteins, 65, 549-554.  
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.  
16301204 K.Arnold, L.Bordoli, J.Kopp, and T.Schwede (2006).
The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling.
  Bioinformatics, 22, 195-201.  
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.  
17043241 S.Chen, Y.Xu, X.Yuan, G.J.Bubley, and S.P.Balk (2006).
Androgen receptor phosphorylation and stabilization in prostate cancer by cyclin-dependent kinase 1.
  Proc Natl Acad Sci U S A, 103, 15969-15974.  
15928920 Y.Jiang, J.Zou, and C.Gui (2005).
Study of a ligand complexed with Cdk2/Cdk4 by computer simulation.
  J Mol Model, 11, 509-515.  
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.  
15123283 F.Becker, K.Murthi, C.Smith, J.Come, N.Costa-Roldán, C.Kaufmann, U.Hanke, C.Degenhart, S.Baumann, W.Wallner, A.Huber, S.Dedier, S.Dill, D.Kinsman, M.Hediger, N.Bockovich, S.Meier-Ewert, A.F.Kluge, and N.Kley (2004).
A three-hybrid approach to scanning the proteome for targets of small molecule kinase inhibitors.
  Chem Biol, 11, 211-223.  
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.  
15031492 M.E.Noble, J.A.Endicott, and L.N.Johnson (2004).
Protein kinase inhibitors: insights into drug design from structure.
  Science, 303, 1800-1805.  
14751090 Y.Dai, and S.Grant (2004).
Small molecule inhibitors targeting cyclin-dependent kinases as anticancer agents.
  Curr Oncol Rep, 6, 123-130.  
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
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.