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PDBsum entry 1fvv

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protein ligands Protein-protein interface(s) links
Transferase, cell cycle PDB id
1fvv
Jmol
Contents
Protein chains
298 a.a. *
260 a.a. *
Ligands
107 ×2
Waters ×129
* Residue conservation analysis
PDB id:
1fvv
Name: Transferase, cell cycle
Title: The structure of cdk2/cyclin a in complex with an oxindole inhibitor
Structure: Cyclin-dependent kinase 2. Chain: a, c. Synonym: cdk2, p33 protein kinase. Engineered: yes. Cyclin a. Chain: b, d. Synonym: cyclin a2. 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 PQS)
Resolution:
2.80Å     R-factor:   0.260     R-free:   0.260
Authors: S.T.Davis,B.G.Benson,H.N.Bramson,D.E.Chapman,S.H.Dickerson, K.M.Dold,D.J.Eberwein,M.Edelstein,S.V.Frye,R.T.Gampe Jr., R.J.Griffin,P.A.Harris,A.M.Hassell,W.D.Holmes,R.N.Hunter, V.B.Knick,K.Lackey,B.Lovejoy,M.J.Luzzio,D.Murray,P.Parker, W.J.Rocque,L.Shewchuk,J.M.Veal,D.H.Walker,L.K.Kuyper
Key ref:
S.T.Davis et al. (2001). Prevention of chemotherapy-induced alopecia in rats by CDK inhibitors. Science, 291, 134-137. PubMed id: 11141566 DOI: 10.1126/science.291.5501.134
Date:
20-Sep-00     Release date:   17-Jan-01    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
Seq:
Struc:
298 a.a.
298 a.a.
Protein chains
Pfam   ArchSchema ?
P20248  (CCNA2_HUMAN) -  Cyclin-A2
Seq:
Struc:
432 a.a.
260 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 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: 10.1126/science.291.5501.134 Science 291:134-137 (2001)
PubMed id: 11141566  
 
 
Prevention of chemotherapy-induced alopecia in rats by CDK inhibitors.
S.T.Davis, B.G.Benson, H.N.Bramson, D.E.Chapman, S.H.Dickerson, K.M.Dold, D.J.Eberwein, M.Edelstein, S.V.Frye, R.T.Gampe Jr, R.J.Griffin, P.A.Harris, A.M.Hassell, W.D.Holmes, R.N.Hunter, V.B.Knick, K.Lackey, B.Lovejoy, M.J.Luzzio, D.Murray, P.Parker, W.J.Rocque, L.Shewchuk, J.M.Veal, D.H.Walker, L.F.Kuyper.
 
  ABSTRACT  
 
Most traditional cytotoxic anticancer agents ablate the rapidly dividing epithelium of the hair follicle and induce alopecia (hair loss). Inhibition of cyclin-dependent kinase 2 (CDK2), a positive regulator of eukaryotic cell cycle progression, may represent a therapeutic strategy for prevention of chemotherapy-induced alopecia (CIA) by arresting the cell cycle and reducing the sensitivity of the epithelium to many cell cycle-active antitumor agents. Potent small-molecule inhibitors of CDK2 were developed using structure-based methods. Topical application of these compounds in a neonatal rat model of CIA reduced hair loss at the site of application in 33 to 50% of the animals. Thus, inhibition of CDK2 represents a potentially useful approach for the prevention of CIA in cancer patients.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. (A) Chemical structures of compounds 1 to 4. (B) X-ray crystallographic structure of CDK2 in complex with compound 3 (15). Atoms are color-coded as follows: protein carbon atoms, green; nitrogen, blue; oxygen, red; sulfur, yellow; and bromine, purple. The carbon atoms of compound 3 are shown in orange. The indolinone (or oxindole) moiety of compound 3 was bound at the back of the ATP site in a manner similar to that found for members of the related series 2 in complex with fibroblast growth factor (FGF) kinase (31). The oxindole amide group of 3 interacted with the strand of protein that connects the two domains of CDK2, donating a hydrogen bond to the backbone carbonyl of Glu81 and accepting a hydrogen bond from the backbone NH of Leu83. The sulfonamidophenylhydrazone group projected toward the opening of the cleft, with the sulfonamide interacting with Asp86. The backbone NH of Asp86 donated a hydrogen bond to one of the sulfonamide oxygen atoms, and the side-chain carboxyl group accepted a hydrogen bond from the sulfonamide amine function. (C) X-ray crystallographic structure of compound 4 bound to CDK2-cyclin A. The carbon atoms of compound 4 are shown in pink. The thiazole nitrogen atom at position 5 of compound 4 accepted a hydrogen bond from Lys33, and the thiazole sulfur atom at position 4 provided hydrophobic interactions with Val18. The pyridyl substituent on the sulfonamide group projected into solvent.
Figure 4.
Fig. 4. Compound 4 prevents hair loss in a neonatal rat model of CIA. Rat pups (13 days of age, actively growing hair) were pretreated 4 hours and 2 hours (t = 4 and 2 hours) with topical application of compound 4 (250 µg; 50 µl of 5 mg/ml DMSO) to the scalp, then injected with etoposide. Etoposide induced total alopecia within 1 week of administration. Hair was assessed and photographed on day 21. The protective activity was schedule dependent. Two applications, 4 hours and 2 hours before etoposide, were optimal for protection. Post-treatment schedules were ineffective in preventing hair loss. Shown are two animals from the untreated group (- etoposide, upper left panel, animals 1 and 2); two animals from DMSO-treated group (+ etoposide, upper right, animals 3 and 4), and five animals from compound 4-treated group (+ etoposide, lower panel, animals 5 to 9). Experiments were repeated at least nine times with five rats per experimental subgroup.
 
  The above figures are reprinted by permission from the AAAs: Science (2001, 291, 134-137) copyright 2001.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21336968 W.Ye, and S.W.Blain (2011).
Chk1 has an essential role in the survival of differentiated cortical neurons in the absence of DNA damage.
  Apoptosis, 16, 449-459.  
20211547 H.Imanishi, D.Tsuruta, C.Tateishi, K.Sugawara, R.Paus, T.Tsuji, M.Ishii, K.Ikeda, H.Kunimoto, K.Nakajima, J.C.Jones, and H.Kobayashi (2010).
Laminin-511, inducer of hair growth, is down-regulated and its suppressor in hair growth, laminin-332 up-regulated in chemotherapy-induced alopecia.
  J Dermatol Sci, 58, 43-54.  
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.  
19046382 H.M.Chen, L.Wang, and S.R.D'Mello (2008).
A chemical compound commonly used to inhibit PKR, {8-(imidazol-4-ylmethylene)-6H-azolidino[5,4-g] benzothiazol-7-one}, protects neurons by inhibiting cyclin-dependent kinase.
  Eur J Neurosci, 28, 2003-2016.  
17269125 H.González-Díaz, L.Saíz-Urra, R.Molina, Y.González-Díaz, and A.Sánchez-González (2007).
Computational chemistry approach to protein kinase recognition using 3D stochastic van der Waals spectral moments.
  J Comput Chem, 28, 1042-1048.  
17634158 K.Nakamura, N.Yokoyama, and I.Igarashi (2007).
Cyclin-dependent kinase inhibitors block erythrocyte invasion and intraerythrocytic development of Babesia bovis in vitro.
  Parasitology, 134, 1347-1353.  
17205374 G.A.Landrum, J.E.Penzotti, and S.Putta (2006).
Feature-map vectors: a new class of informative descriptors for computational drug discovery.
  J Comput Aided Mol Des, 20, 751-762.  
16584130 J.Sridhar, N.Akula, and N.Pattabiraman (2006).
Selectivity and potency of cyclin-dependent kinase inhibitors.
  AAPS J, 8, E204-E221.  
15905797 A.Elis, D.Blickstein, Y.Manor, and M.Lishner (2005).
Association between alopecia and response to chemotherapy in patients with Hodgkin lymphoma.
  Ther Drug Monit, 27, 287-289.  
15931503 H.Dureja, and A.K.Madan (2005).
Topochemical models for prediction of cyclin-dependent kinase 2 inhibitory activity of indole-2-ones.
  J Mol Model, 11, 525-531.  
15836613 K.Johnson, L.Liu, N.Majdzadeh, C.Chavez, P.C.Chin, B.Morrison, L.Wang, J.Park, P.Chugh, H.M.Chen, and S.R.D'Mello (2005).
Inhibition of neuronal apoptosis by the cyclin-dependent kinase inhibitor GW8510: identification of 3' substituted indolones as a scaffold for the development of neuroprotective drugs.
  J Neurochem, 93, 538-548.  
14993903 B.B.Zhou, and J.Bartek (2004).
Targeting the checkpoint kinases: chemosensitization versus chemoprotection.
  Nat Rev Cancer, 4, 216-225.  
15350195 D.Finlay, S.Patel, L.M.Dickson, N.Shpiro, R.Marquez, C.J.Rhodes, and C.Sutherland (2004).
Glycogen synthase kinase-3 regulates IGFBP-1 gene transcription through the thymine-rich insulin response element.
  BMC Mol Biol, 5, 15.  
15271198 D.J.Wolgemuth, K.M.Lele, V.Jobanputra, and G.Salazar (2004).
The A-type cyclins and the meiotic cell cycle in mammalian male germ cells.
  Int J Androl, 27, 192-199.  
15572662 L.K.Pierson-Mullany, and C.A.Lange (2004).
Phosphorylation of progesterone receptor serine 400 mediates ligand-independent transcriptional activity in response to activation of cyclin-dependent protein kinase 2.
  Mol Cell Biol, 24, 10542-10557.  
15173837 P.Cohen, and M.Goedert (2004).
GSK3 inhibitors: development and therapeutic potential.
  Nat Rev Drug Discov, 3, 479-487.  
15617561 R.Paus, and K.Foitzik (2004).
In search of the "hair cycle clock": a guided tour.
  Differentiation, 72, 489-511.  
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.  
12894998 V.A.Botchkarev (2003).
Molecular mechanisms of chemotherapy-induced hair loss.
  J Investig Dermatol Symp Proc, 8, 72-75.  
11927285 E.A.Sausville (2002).
Complexities in the development of cyclin-dependent kinase inhibitor drugs.
  Trends Mol Med, 8, S32-S37.  
12402499 E.G.Nabel (2002).
CDKs and CKIs: molecular targets for tissue remodelling.
  Nat Rev Drug Discov, 1, 587-598.  
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.  
11857351 N.Villerbu, A.M.Gaben, G.Redeuilh, and J.Mester (2002).
Cellular effects of purvalanol A: a specific inhibitor of cyclin-dependent kinase activities.
  Int J Cancer, 97, 761-769.  
12133723 P.L.Toogood (2002).
Progress toward the development of agents to modulate the cell cycle.
  Curr Opin Chem Biol, 6, 472-478.  
12191603 R.A.Engh, and D.Bossemeyer (2002).
Structural aspects of protein kinase control-role of conformational flexibility.
  Pharmacol Ther, 93, 99.  
11960696 S.Ortega, M.Malumbres, and M.Barbacid (2002).
Cyclin D-dependent kinases, INK4 inhibitors and cancer.
  Biochim Biophys Acta, 1602, 73-87.  
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.  
11673689 D.Sampath, and W.Plunkett (2001).
Design of new anticancer therapies targeting cell cycle checkpoint pathways.
  Curr Opin Oncol, 13, 484-490.  
11425637 G.Cotsarelis, and S.E.Millar (2001).
Towards a molecular understanding of hair loss and its treatment.
  Trends Mol Med, 7, 293-301.  
11687495 M.A.Shogren-Knaak, P.J.Alaimo, and K.M.Shokat (2001).
Recent advances in chemical approaches to the study of biological systems.
  Annu Rev Cell Dev Biol, 17, 405-433.  
11752010 N.Sato, P.L.Leopold, and R.G.Crystal (2001).
Effect of adenovirus-mediated expression of Sonic hedgehog gene on hair regrowth in mice with chemotherapy-induced alopecia.
  J Natl Cancer Inst, 93, 1858-1864.  
12030783 S.Wadler (2001).
Perspectives for cancer therapies with cdk2 inhibitors.
  Drug Resist Updat, 4, 347-367.  
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.