spacer
spacer

PDBsum entry 3kvx

Go to PDB code: 
protein ligands links
Transferase PDB id
3kvx
Jmol
Contents
Protein chain
330 a.a. *
Ligands
FMY
Waters ×27
* Residue conservation analysis
PDB id:
3kvx
Name: Transferase
Title: Jnk3 bound to aminopyrimidine inhibitor, sr-3562
Structure: Mitogen-activated protein kinase 10. Chain: a. Fragment: residues 39-402. Synonym: stress-activated protein kinase jnk3, c-jun n-term kinase 3, map kinase p49 3f12. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: mapk10, jnk3, jnk3a, prkm10. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.40Å     R-factor:   0.222     R-free:   0.269
Authors: J.E.Habel,J.D.Laughlin,P.Lograsso
Key ref: T.Kamenecka et al. (2010). Synthesis, biological evaluation, X-ray structure, and pharmacokinetics of aminopyrimidine c-jun-N-terminal kinase (JNK) inhibitors. J Med Chem, 53, 419-431. PubMed id: 19947601
Date:
30-Nov-09     Release date:   22-Dec-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.
330 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 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    
 
 
J Med Chem 53:419-431 (2010)
PubMed id: 19947601  
 
 
Synthesis, biological evaluation, X-ray structure, and pharmacokinetics of aminopyrimidine c-jun-N-terminal kinase (JNK) inhibitors.
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, P.V.LoGrasso.
 
  ABSTRACT  
 
Given the significant body of data supporting an essential role for c-jun-N-terminal kinase (JNK) in neurodegenerative disorders, we set out to develop highly selective JNK inhibitors with good cell potency and good brain penetration properties. The structure-activity relationships (SAR) around a series of aminopyrimidines were evaluated utilizing biochemical and cell-based assays to measure JNK inhibition and brain penetration in mice. Microsomal stability in three species, P450 inhibition, inhibition of generation of reactive oxygen species (ROS), and pharmacokinetics in rats were also measured. Compounds 9g, 9i, 9j, and 9l had greater than 135-fold selectivity over p38, and cell-based IC(50) values < 100 nM. Moreover, compound 9l showed an IC(50) = 0.8 nM for inhibition of ROS and had good pharmacokinetic properties in rats along with a brain-to-plasma ratio of 0.75. These results suggest that biaryl substituted aminopyrimidines represented by compound 9l may serve as the first small molecule inhibitors to test efficacy of JNK inhibitors in neurodegenerative disorders.
 

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.  
21458276 S.K.De, E.Barile, V.Chen, J.L.Stebbins, J.F.Cellitti, T.Machleidt, C.B.Carlson, L.Yang, R.Dahl, and M.Pellecchia (2011).
Design, synthesis, and structure-activity relationship studies of thiophene-3-carboxamide derivatives as dual inhibitors of the c-Jun N-terminal kinase.
  Bioorg Med Chem, 19, 2582-2588.  
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.