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PDBsum entry 3bht

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protein ligands metals Protein-protein interface(s) links
Transferase PDB id
3bht
Jmol
Contents
Protein chains
298 a.a. *
262 a.a. *
271 a.a. *
Ligands
MFR ×2
SGM ×3
Metals
_MG ×2
Waters ×1078
* Residue conservation analysis
PDB id:
3bht
Name: Transferase
Title: Structure of phosphorylated thr160 cdk2/cyclin a in complex inhibitor meriolin 3
Structure: Cell division protein kinase 2. Chain: a, c. Synonym: p33 protein kinase, cdk2. Engineered: yes. Cyclin-a2. Chain: b, d. Fragment: unp residues 169-430. Synonym: cyclin-a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: cdk2. Expressed in: escherichia coli. Expression_system_taxid: 562. Bos taurus. Cattle. Organism_taxid: 9913.
Resolution:
2.00Å     R-factor:   0.183     R-free:   0.220
Authors: A.Echalier,K.Bettayeb,Y.Ferandin,O.Lozach,M.Clement,A.Valett F.Liger,B.Marquet,J.C.Morris,J.A.Endicott,B.Joseph,L.Meijer
Key ref: K.Bettayeb et al. (2007). Meriolins, a new class of cell death inducing kinase inhibitors with enhanced selectivity for cyclin-dependent kinases. Cancer Res, 67, 8325-8334. PubMed id: 17804748 DOI: 10.1158/0008-5472.CAN-07-1826
Date:
29-Nov-07     Release date:   12-Feb-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
Seq:
Struc:
298 a.a.
298 a.a.*
Protein chains
Pfam   ArchSchema ?
P30274  (CCNA2_BOVIN) -  Cyclin-A2
Seq:
Struc:
430 a.a.
262 a.a.
Protein chain
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
Seq:
Struc:
298 a.a.
271 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 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: 10.1158/0008-5472.CAN-07-1826 Cancer Res 67:8325-8334 (2007)
PubMed id: 17804748  
 
 
Meriolins, a new class of cell death inducing kinase inhibitors with enhanced selectivity for cyclin-dependent kinases.
K.Bettayeb, O.M.Tirado, S.Marionneau-Lambot, Y.Ferandin, O.Lozach, J.C.Morris, S.Mateo-Lozano, P.Drueckes, C.Schächtele, M.H.Kubbutat, F.Liger, B.Marquet, B.Joseph, A.Echalier, J.A.Endicott, V.Notario, L.Meijer.
 
  ABSTRACT  
 
Protein kinases represent promising anticancer drug targets. We describe here the meriolins, a new family of inhibitors of cyclin-dependent kinases (CDK). Meriolins represent a chemical structural hybrid between meridianins and variolins, two families of kinase inhibitors extracted from various marine invertebrates. Variolin B is currently in preclinical evaluation as an antitumor agent. A selectivity study done on 32 kinases showed that, compared with variolin B, meriolins display enhanced specificity toward CDKs, with marked potency on CDK2 and CDK9. The structures of pCDK2/cyclin A/variolin B and pCDK2/cyclin A/meriolin 3 complexes reveal that the two inhibitors bind within the ATP binding site of the kinase, but in different orientations. Meriolins display better antiproliferative and proapoptotic properties in human tumor cell cultures than their parent molecules, meridianins and variolins. Phosphorylation at CDK1, CDK4, and CDK9 sites on, respectively, protein phosphatase 1alpha, retinoblastoma protein, and RNA polymerase II is inhibited in neuroblastoma SH-SY5Y cells exposed to meriolins. Apoptosis triggered by meriolins is accompanied by rapid Mcl-1 down-regulation, cytochrome c release, and activation of caspases. Meriolin 3 potently inhibits tumor growth in two mouse xenograft cancer models, namely, Ewing's sarcoma and LS174T colorectal carcinoma. Meriolins thus constitute a new CDK inhibitory scaffold, with promising antitumor activity, derived from molecules initially isolated from marine organisms.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21333571 C.Fang, Z.Xiao, and Z.Guo (2011).
Generation and validation of the first predictive pharmacophore model for cyclin-dependent kinase 9 inhibitors.
  J Mol Graph Model, 29, 800-808.  
  20628499 L.Carpio, Z.Klase, W.Coley, I.Guendel, S.Choi, R.Van Duyne, A.Narayanan, K.Kehn-Hall, L.Meijer, and F.Kashanchi (2010).
microRNA machinery is an integral component of drug-induced transcription inhibition in HIV-1 infection.
  J RNAi Gene Silencing, 6, 386-400.  
20223596 M.Wachtel, and B.W.Schäfer (2010).
Targets for cancer therapy in childhood sarcomas.
  Cancer Treat Rev, 36, 318-327.  
20559487 P.M.Pauletti, L.S.Cintra, C.G.Braguine, A.A.da Silva Filho, M.L.Silva, W.R.Cunha, and A.H.Januário (2010).
Halogenated indole alkaloids from marine invertebrates.
  Mar Drugs, 8, 1526-1549.  
19775281 A.E.Leitch, C.Haslett, and A.G.Rossi (2009).
Cyclin-dependent kinase inhibitor drugs as potential novel anti-inflammatory and pro-resolution agents.
  Br J Pharmacol, 158, 1004-1016.  
19220318 A.G.Villaseñor, R.Kondru, H.Ho, S.Wang, E.Papp, D.Shaw, J.W.Barnett, M.F.Browner, and A.Kuglstatter (2009).
Structural insights for design of potent spleen tyrosine kinase inhibitors from crystallographic analysis of three inhibitor complexes.
  Chem Biol Drug Des, 73, 466-470.
PDB codes: 3fqe 3fqh 3fqs
19177222 J.W.Blunt, B.R.Copp, W.P.Hu, M.H.Munro, P.T.Northcote, and M.R.Prinsep (2009).
Marine natural products.
  Nat Prod Rep, 26, 170-244.  
18690090 E.Rossignol, E.Debiton, D.Fabbro, P.Moreau, M.Prudhomme, and F.Anizon (2008).
In-vitro antiproliferative activities and kinase inhibitory potencies of meridianin derivatives.
  Anticancer Drugs, 19, 789-792.  
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.