spacer
spacer

PDBsum entry 1w0x

Go to PDB code: 
protein ligands links
Transferase PDB id
1w0x
Jmol
Contents
Protein chain
280 a.a. *
Ligands
OLO
Waters ×76
* Residue conservation analysis
PDB id:
1w0x
Name: Transferase
Title: Crystal structure of human cdk2 in complex with the inhibitor olomoucine.
Structure: Cyclin-dependent kinase 2. Chain: c. Synonym: p33 protein kinase, cdk2. Engineered: yes. Other_details: inhibitor bound in pocket between 2 domains
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
Resolution:
2.20Å     R-factor:   0.190     R-free:   0.270
Authors: U.Schulze-Gahmen,L.Meijer,S.-H.Kim
Key ref: U.Schulze-Gahmen et al. (1995). Multiple modes of ligand recognition: crystal structures of cyclin-dependent protein kinase 2 in complex with ATP and two inhibitors, olomoucine and isopentenyladenine. Proteins, 22, 378-391. PubMed id: 7479711
Date:
14-Jun-04     Release date:   14-Jan-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
Seq:
Struc:
298 a.a.
280 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: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
=
ADP
Bound ligand (Het Group name = OLO)
matches with 44.12% similarity
+ 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   27 terms 
  Biochemical function     nucleotide binding     12 terms  

 

 
    reference    
 
 
Proteins 22:378-391 (1995)
PubMed id: 7479711  
 
 
Multiple modes of ligand recognition: crystal structures of cyclin-dependent protein kinase 2 in complex with ATP and two inhibitors, olomoucine and isopentenyladenine.
U.Schulze-Gahmen, J.Brandsen, H.D.Jones, D.O.Morgan, L.Meijer, J.Vesely, S.H.Kim.
 
  ABSTRACT  
 
Cyclin-dependent kinases (CDKs) are conserved regulators of the eukaryotic cell cycle with different isoforms controlling specific phases of the cell cycle. Mitogenic or growth inhibitory signals are mediated, respectively, by activation or inhibition of CDKs which phosphorylate proteins associated with the cell cycle. The central role of CDKs in cell cycle regulation makes them a potential new target for inhibitory molecules with anti-proliferative and/or anti-neoplastic effects. We describe the crystal structures of the complexes of CDK2 with a weakly specific CDK inhibitor, N6-(delta 2-isopentenyl)adenine, and a strongly specific inhibitor, olomoucine. Both inhibitors are adenine derivatives and bind in the adenine binding pocket of CDK2, but in an unexpected and different orientation from the adenine of the authentic ligand ATP. The N6-benzyl substituent in olomoucine binds outside the conserved binding pocket and is most likely responsible for its specificity. The structural information from the CDK2-olomoucine complex will be useful in directing the search for the next generation inhibitors with improved properties.
 

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.  
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.  
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.  
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.  
19185282 P.Lahiry, J.Wang, J.F.Robinson, J.P.Turowec, D.W.Litchfield, M.B.Lanktree, G.B.Gloor, E.G.Puffenberger, K.A.Strauss, M.B.Martens, D.A.Ramsay, C.A.Rupar, V.Siu, and R.A.Hegele (2009).
A multiplex human syndrome implicates a key role for intestinal cell kinase in development of central nervous, skeletal, and endocrine systems.
  Am J Hum Genet, 84, 134-147.  
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
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.  
17339323 L.Spíchal, V.Krystof, M.Paprskárová, R.Lenobel, J.Styskala, P.Binarová, V.Cenklová, L.De Veylder, D.Inzé, G.Kontopidis, P.M.Fischer, T.Schmülling, and M.Strnad (2007).
Classical anticytokinins do not interact with cytokinin receptors but inhibit cyclin-dependent kinases.
  J Biol Chem, 282, 14356-14363.  
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.  
18077363 O.Fedorov, B.Marsden, V.Pogacic, P.Rellos, S.Müller, A.N.Bullock, J.Schwaller, M.Sundström, and S.Knapp (2007).
A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases.
  Proc Natl Acad Sci U S A, 104, 20523-20528.
PDB code: 2j2i
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.  
17243097 Z.Zhu, Q.Zhang, Z.Yu, L.Zhang, D.Tian, S.Zhu, B.Bu, M.Xie, and W.Wang (2007).
Inhibiting cell cycle progression reduces reactive astrogliosis initiated by scratch injury in vitro and by cerebral ischemia in vivo.
  Glia, 55, 546-558.  
17095602 A.P.Kornev, N.M.Haste, S.S.Taylor, and L.F.Eyck (2006).
Surface comparison of active and inactive protein kinases identifies a conserved activation mechanism.
  Proc Natl Acad Sci U S A, 103, 17783-17788.  
16584130 J.Sridhar, N.Akula, and N.Pattabiraman (2006).
Selectivity and potency of cyclin-dependent kinase inhibitors.
  AAPS J, 8, E204-E221.  
16827651 M.K.Bernhard, and K.Ulrich (2006).
Rt-PCR study of purinergic P2 receptors in hematopoietic cell lines.
  Biochemistry (Mosc), 71, 607-611.  
16354836 D.Tobi, and I.Bahar (2005).
Structural changes involved in protein binding correlate with intrinsic motions of proteins in the unbound state.
  Proc Natl Acad Sci U S A, 102, 18908-18913.  
16075305 K.A.Rossi, J.A.Markwalder, S.P.Seitz, C.H.Chang, S.Cox, M.D.Boisclair, L.Brizuela, S.L.Brenner, and P.F.Stouten (2005).
Understanding and modulating cyclin-dependent kinase inhibitor specificity: molecular modeling and biochemical evaluation of pyrazolopyrimidinones as CDK2/cyclin A and CDK4/cyclin D1 inhibitors.
  J Comput Aided Mol Des, 19, 111-122.  
16096806 K.K.Manhani, H.A.Arcuri, N.J.da Silveira, H.B.Uchôa, W.F.de Azevedo, and F.Canduri (2005).
Molecular models of protein kinase 6 from Plasmodium falciparum.
  J Mol Model, 12, 42-48.  
15133164 I.Bártová, M.Otyepka, Z.Kríz, and J.Koca (2004).
Activation and inhibition of cyclin-dependent kinase-2 by phosphorylation; a molecular dynamics study reveals the functional importance of the glycine-rich loop.
  Protein Sci, 13, 1449-1457.  
15048820 Z.Kríz, M.Otyepka, I.Bártová, and J.Koca (2004).
Analysis of CDK2 active-site hydration: a method to design new inhibitors.
  Proteins, 55, 258-274.  
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
12548283 T.A.Young, B.Delagoutte, J.A.Endrizzi, A.M.Falick, and T.Alber (2003).
Structure of Mycobacterium tuberculosis PknB supports a universal activation mechanism for Ser/Thr protein kinases.
  Nat Struct Biol, 10, 168-174.
PDB code: 1mru
12191602 D.Fabbro, S.Ruetz, E.Buchdunger, S.W.Cowan-Jacob, G.Fendrich, J.Liebetanz, J.Mestan, T.O'Reilly, P.Traxler, B.Chaudhuri, H.Fretz, J.Zimmermann, T.Meyer, G.Caravatti, P.Furet, and P.W.Manley (2002).
Protein kinases as targets for anticancer agents: from inhibitors to useful drugs.
  Pharmacol Ther, 93, 79-98.  
12047871 G.Scapin (2002).
Structural biology in drug design: selective protein kinase inhibitors.
  Drug Discov Today, 7, 601-611.  
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
11933058 V.Cappello, A.Tramontano, and U.Koch (2002).
Classification of proteins based on the properties of the ligand-binding site: the case of adenine-binding proteins.
  Proteins, 47, 106-115.  
12685824 Y.Honma, and Y.Ishii (2002).
Differentiation of human myeloid leukemia cells by plant redifferentiation-inducing hormones.
  Leuk Lymphoma, 43, 1729-1735.  
11306297 A.C.Bishop, O.Buzko, and K.M.Shokat (2001).
Magic bullets for protein kinases.
  Trends Cell Biol, 11, 167-172.  
11325745 M.Fiorini, R.McKendry, M.A.Cooper, T.Rayment, and C.Abell (2001).
Chemical force microscopy with active enzymes.
  Biophys J, 80, 2471-2476.  
  11604388 P.M.Clare, R.A.Poorman, L.C.Kelley, K.D.Watenpaugh, C.A.Bannow, and K.L.Leach (2001).
The cyclin-dependent kinases cdk2 and cdk5 act by a random, anticooperative kinetic mechanism.
  J Biol Chem, 276, 48292-48299.
PDB code: 1jsv
11259469 R.Soni, T.O'Reilly, P.Furet, L.Muller, C.Stephan, S.Zumstein-Mecker, H.Fretz, D.Fabbro, and B.Chaudhuri (2001).
Selective in vivo and in vitro effects of a small molecule inhibitor of cyclin-dependent kinase 4.
  J Natl Cancer Inst, 93, 436-446.  
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.  
10666240 L.M.Schang, A.Rosenberg, and P.A.Schaffer (2000).
Roscovitine, a specific inhibitor of cellular cyclin-dependent kinases, inhibits herpes simplex virus DNA synthesis in the presence of viral early proteins.
  J Virol, 74, 2107-2120.  
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
10893547 L.Sun, and G.McMahon (2000).
Inhibition of tumor angiogenesis by synthetic receptor tyrosine kinase inhibitors.
  Drug Discov Today, 5, 344-353.  
10454194 J.M.Sowadski, L.F.Epstein, L.Lankiewicz, and R.Karlsson (1999).
Conformational diversity of catalytic cores of protein kinases.
  Pharmacol Ther, 82, 157-164.  
  9971799 L.M.Schang, A.Rosenberg, and P.A.Schaffer (1999).
Transcription of herpes simplex virus immediate-early and early genes is inhibited by roscovitine, an inhibitor specific for cellular cyclin-dependent kinases.
  J Virol, 73, 2161-2172.  
10072351 M.D.Garrett, and A.Fattaey (1999).
CDK inhibition and cancer therapy.
  Curr Opin Genet Dev, 9, 104-111.  
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.  
9990463 P.Imbach, H.G.Capraro, P.Furet, H.Mett, T.Meyer, and J.Zimmermann (1999).
2,6,9-trisubstituted purines: optimization towards highly potent and selective CDK1 inhibitors.
  Bioorg Med Chem Lett, 9, 91-96.  
10454197 P.Traxler, and P.Furet (1999).
Strategies toward the design of novel and selective protein tyrosine kinase inhibitors.
  Pharmacol Ther, 82, 195-206.  
10454192 S.S.Taylor, E.Radzio-Andzelm, Madhusudan, X.Cheng, L.Ten Eyck, and N.Narayana (1999).
Catalytic subunit of cyclic AMP-dependent protein kinase: structure and dynamics of the active site cleft.
  Pharmacol Ther, 82, 133-141.  
10375538 Y.T.Chang, N.S.Gray, G.R.Rosania, D.P.Sutherlin, S.Kwon, T.C.Norman, R.Sarohia, M.Leost, L.Meijer, and P.G.Schultz (1999).
Synthesis and application of functionally diverse 2,6,9-trisubstituted purine libraries as CDK inhibitors.
  Chem Biol, 6, 361-375.  
15992004 K.R.Webster (1998).
The therapeutic potential of targeting the cell cycle.
  Expert Opin Investig Drugs, 7, 865-887.  
  9621021 L.M.Schang, J.Phillips, and P.A.Schaffer (1998).
Requirement for cellular cyclin-dependent kinases in herpes simplex virus replication and transcription.
  J Virol, 72, 5626-5637.  
9871700 S.Sasaki, T.Hashimoto, N.Obana, H.Yasuda, Y.Uehara, and M.Maeda (1998).
Design of new inhibitors for cdc2 kinase based on a multiple pseudosubstrate structure.
  Bioorg Med Chem Lett, 8, 1019-1022.  
9753691 Z.Wang, B.J.Canagarajah, J.C.Boehm, S.Kassisà, M.H.Cobb, P.R.Young, S.Abdel-Meguid, J.L.Adams, and E.J.Goldsmith (1998).
Structural basis of inhibitor selectivity in MAP kinases.
  Structure, 6, 1117-1128.
PDB codes: 1a9u 1bl6 1bl7 1bmk 3erk 4erk
9095200 L.Tong, S.Pav, D.M.White, S.Rogers, K.M.Crane, C.L.Cywin, M.L.Brown, and C.A.Pargellis (1997).
A highly specific inhibitor of human p38 MAP kinase binds in the ATP pocket.
  Nat Struct Biol, 4, 311-316.
PDB code: 1ian
9667861 S.S.Taylor, and E.Radzio-Andzelm (1997).
Protein kinase inhibition: natural and synthetic variations on a theme.
  Curr Opin Chem Biol, 1, 219-226.  
9122194 Z.Wang, P.C.Harkins, R.J.Ulevitch, J.Han, M.H.Cobb, and E.J.Goldsmith (1997).
The structure of mitogen-activated protein kinase p38 at 2.1-A resolution.
  Proc Natl Acad Sci U S A, 94, 2327-2332.
PDB code: 1p38
8910383 A.Borgne, and L.Meijer (1996).
Sequential dephosphorylation of p34(cdc2) on Thr-14 and Tyr-15 at the prophase/metaphase transition.
  J Biol Chem, 271, 27847-27854.  
8824261 R.A.Engh, A.Girod, V.Kinzel, R.Huber, and D.Bossemeyer (1996).
Crystal structures of catalytic subunit of cAMP-dependent protein kinase in complex with isoquinolinesulfonyl protein kinase inhibitors H7, H8, and H89. Structural implications for selectivity.
  J Biol Chem, 271, 26157-26164.
PDB codes: 1ydr 1yds 1ydt
8692811 R.M.Xu, G.Carmel, J.Kuret, and X.Cheng (1996).
Structural basis for selectivity of the isoquinoline sulfonamide family of protein kinase inhibitors.
  Proc Natl Acad Sci U S A, 93, 6308-6313.
PDB code: 2csn
8610110 W.F.De Azevedo, H.J.Mueller-Dieckmann, U.Schulze-Gahmen, P.J.Worland, E.Sausville, and S.H.Kim (1996).
Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase.
  Proc Natl Acad Sci U S A, 93, 2735-2740.  
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.