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PDBsum entry 3jpv

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protein ligands links
Transferase / transferase inhibitor PDB id
3jpv
Jmol PyMol
Contents
Protein chain
273 a.a. *
Ligands
LYS-ARG-ARG-ARG-
HIS-PRO-SER
1DR
Waters ×161
* Residue conservation analysis
PDB id:
3jpv
Name: Transferase / transferase inhibitor
Title: Crystal structure of human proto-oncogene serine threonine k (pim1) in complex with a consensus peptide and a pyrrolo[2, a]carbazole ligand
Structure: Proto-oncogene serine/threonine-protein kinase pi chain: a. Engineered: yes. Peptide (pimtide) arkrrrhpsgppta. Chain: b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pim1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes
Resolution:
2.35Å     R-factor:   0.176     R-free:   0.226
Authors: P.Filippakopoulos,A.N.Bullock,O.Fedorov,R.Akue-Gedu,E.Rossig S.Azzaro,J.Bain,P.Cohen,M.Prudhomme,P.Moreau,F.Amizon,F.Von C.H.Arrowsmith,J.Weigelt,A.Edwards,C.Bountra,S.Knapp,Struct Genomics Consortium (Sgc)
Key ref: R.Akué-Gédu et al. (2009). Synthesis, kinase inhibitory potencies, and in vitro antiproliferative evaluation of new Pim kinase inhibitors. J Med Chem, 52, 6369-6381. PubMed id: 19788246
Date:
04-Sep-09     Release date:   27-Oct-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P11309  (PIM1_HUMAN) -  Serine/threonine-protein kinase pim-1
Seq:
Struc:
404 a.a.
273 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.2.7.11.1  - Non-specific serine/threonine protein 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!
  Biological process     negative regulation of apoptotic process   2 terms 
  Biochemical function     protein kinase activity     3 terms  

 

 
    reference    
 
 
J Med Chem 52:6369-6381 (2009)
PubMed id: 19788246  
 
 
Synthesis, kinase inhibitory potencies, and in vitro antiproliferative evaluation of new Pim kinase inhibitors.
R.Akué-Gédu, E.Rossignol, S.Azzaro, S.Knapp, P.Filippakopoulos, A.N.Bullock, J.Bain, P.Cohen, M.Prudhomme, F.Anizon, P.Moreau.
 
  ABSTRACT  
 
Members of the Pim kinase family have been identified as promising targets for the development of antitumor agents. After a screening of pyrrolo[2,3-a]- and [3,2-a]carbazole derivatives toward 66 protein kinases, we identified pyrrolo[2,3-a]carbazole as a new scaffold to design potent Pim kinase inhibitors. In particular, compound 9 was identified as a low nM selective Pim inhibitor. Additionally, several pyrrolo[2,3-a]carbazole derivatives showed selectivity for Pim-1 and Pim-3 over Pim-2. In vitro antiproliferative activities of 9 and 28, the most potent Pim inhibitors identified, were evaluated toward three human solid cancer cell lines (PA1, PC3, and DU145) and one human fibroblast primary culture, revealing IC50 values in the micromolar range. Finally, the crystal structure of Pim-1 complexed with lead compound 9 was determined. The structure revealed a non-ATP mimetic binding mode with no hydrogen bonds formed with the kinase hinge region and explained the selectivity of pyrrolo[2,3-a]carbazole derivatives for Pim kinases.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21187426 Z.Beharry, S.Mahajan, M.Zemskova, Y.W.Lin, B.G.Tholanikunnel, Z.Xia, C.D.Smith, and A.S.Kraft (2011).
The Pim protein kinases regulate energy metabolism and cell growth.
  Proc Natl Acad Sci U S A, 108, 528-533.  
20734015 M.Laronze-Cochard, F.Cochard, E.Daras, A.Lansiaux, B.Brassart, E.Vanquelef, E.Prost, J.M.Nuzillard, B.Baldeyrou, J.F.Goosens, O.Lozach, L.Meijer, J.F.Riou, E.Henon, and J.Sapi (2010).
Synthesis and biological evaluation of new penta- and heptacyclic indolo- and quinolinocarbazole ring systems obtained via Pd(0) catalysed reductive N-heteroannulation.
  Org Biomol Chem, 8, 4625-4636.  
20958956 N.M.Santio, R.L.Vahakoski, E.M.Rainio, J.A.Sandholm, S.S.Virtanen, M.Prudhomme, F.Anizon, P.Moreau, and P.J.Koskinen (2010).
Pim-selective inhibitor DHPCC-9 reveals Pim kinases as potent stimulators of cancer cell migration and invasion.
  Mol Cancer, 9, 279.  
20919829 N.S.Magnuson, Z.Wang, G.Ding, and R.Reeves (2010).
Why target PIM1 for cancer diagnosis and treatment?
  Future Oncol, 6, 1461-1478.  
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.

 

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