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PDBsum entry 3fi2

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protein ligands links
Transferase PDB id
3fi2
Jmol
Contents
Protein chain
328 a.a. *
Ligands
JK1
EDO
Waters ×155
* Residue conservation analysis
PDB id:
3fi2
Name: Transferase
Title: Crystal structure of jnk3 with amino-pyrazole inhibitor, sr- 3451
Structure: Mitogen-activated protein kinase 10. Chain: a. Fragment: unp residues 39-402. Synonym: stress-activated protein kinase jnk3, c-jun n- terminal kinase 3, map kinase p49 3f12. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: jnk3, jnk3a, mapk10, prkm10. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.28Å     R-factor:   0.189     R-free:   0.267
Authors: J.E.Habel
Key ref:
T.Kamenecka et al. (2009). Structure-Activity Relationships and X-ray Structures Describing the Selectivity of Aminopyrazole Inhibitors for c-Jun N-terminal Kinase 3 (JNK3) over p38. J Biol Chem, 284, 12853-12861. PubMed id: 19261605 DOI: 10.1074/jbc.M809430200
Date:
10-Dec-08     Release date:   03-Mar-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P53779  (MK10_HUMAN) -  Mitogen-activated protein kinase 10
Seq:
Struc:
464 a.a.
328 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 8 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.2.7.11.24  - Mitogen-activated 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     protein phosphorylation   1 term 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     5 terms  

 

 
    reference    
 
 
DOI no: 10.1074/jbc.M809430200 J Biol Chem 284:12853-12861 (2009)
PubMed id: 19261605  
 
 
Structure-Activity Relationships and X-ray Structures Describing the Selectivity of Aminopyrazole Inhibitors for c-Jun N-terminal Kinase 3 (JNK3) over p38.
T.Kamenecka, J.Habel, D.Duckett, W.Chen, Y.Y.Ling, B.Frackowiak, R.Jiang, Y.Shin, X.Song, P.Lograsso.
 
  ABSTRACT  
 
c-Jun N-terminal kinase 3alpha1 (JNK3alpha1) is a mitogen-activated protein kinase family member expressed primarily in the brain that phosphorylates protein transcription factors, including c-Jun and activating transcription factor-2 (ATF-2) upon activation by a variety of stress-based stimuli. In this study, we set out to design JNK3-selective inhibitors that had >1000-fold selectivity over p38, another closely related mitogen-activated protein kinase family member. To do this we employed traditional medicinal chemistry principles coupled with structure-based drug design. Inhibitors from the aminopyrazole class, such as SR-3576, were found to be very potent JNK3 inhibitors (IC(50) = 7 nm) with >2800-fold selectivity over p38 (p38 IC(50) > 20 mum) and had cell-based potency of approximately 1 mum. In contrast, indazole-based inhibitors exemplified by SR-3737 were potent inhibitors of both JNK3 (IC(50) = 12 nm) and p38 (IC(50) = 3 nm). These selectivity differences between the indazole class and the aminopyrazole class came despite nearly identical binding (root mean square deviation = 0.33 A) of these two compound classes to JNK3. The structural features within the compounds giving rise to the selectivity in the aminopyrazole class include the highly planar nature of the pyrazole, N-linked phenyl structures, which better occupied the smaller active site of JNK3 compared with the larger active site of p38.
 
  Selected figure(s)  
 
Figure 1.
Overlay of SR-3737 (magenta) and SR-3451 (cyan) structures. JNK3 (green) is shown as a schematic ribbon diagram with important residues highlighted in stick format and labeled. Hydrogen bonds between the compounds and the main-chain atoms of Met-149 are shown as black dotted lines. The figures was generated by using PyMOL.
Figure 2.
Overlay of SR-3737 (magenta) with compound 14e (orange) from PDB ID 1M7Q (32). p38 (blue) is shown as a schematic ribbon diagram with homologous JNK3 highlighted residues from Fig. 1 in stick format and labeled using p38 numbering. The figure was generated by using PyMOL.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2009, 284, 12853-12861) copyright 2009.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21185177 R.Noël, Y.Shin, X.Song, Y.He, M.Koenig, W.Chen, Y.Y.Ling, L.Lin, C.H.Ruiz, P.LoGrasso, M.D.Cameron, D.R.Duckett, and T.M.Kamenecka (2011).
Synthesis and SAR of 4-(pyrazol-3-yl)-pyridines as novel c-jun N-terminal kinase inhibitors.
  Bioorg Med Chem Lett, 21, 2732-2735.  
21108268 M.Goettert, V.Schattel, P.Koch, I.Merfort, and S.Laufer (2010).
Biological evaluation and structural determinants of p38α mitogen-activated-protein kinase and c-Jun-N-terminal kinase 3 inhibition by flavonoids.
  Chembiochem, 11, 2579-2588.  
19947601 T.Kamenecka, R.Jiang, X.Song, D.Duckett, W.Chen, Y.Y.Ling, J.Habel, J.D.Laughlin, J.Chambers, M.Figuera-Losada, M.D.Cameron, L.Lin, C.H.Ruiz, and P.V.LoGrasso (2010).
Synthesis, biological evaluation, X-ray structure, and pharmacokinetics of aminopyrimidine c-jun-N-terminal kinase (JNK) inhibitors.
  J Med Chem, 53, 419-431.
PDB code: 3kvx
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