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PDBsum entry 3itz

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Transferase PDB id
3itz
Jmol
Contents
Protein chain
357 a.a. *
Ligands
P66
Waters ×92
* Residue conservation analysis
PDB id:
3itz
Name: Transferase
Title: Crystal structure of p38a mitogen-activated protein kinase in complex with a pyrazolopyridazine inhibitor
Structure: Mitogen-activated protein kinase 14. Chain: a. Synonym: mitogen-activated protein kinase p38 alpha, map kinase p38 alpha, cytokine suppressive anti-inflammatory drug-binding protein, csaid-binding protein, csbp, max- interacting protein 2, map kinase mxi2, sapk2a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: mapk14, csbp, csbp1, csbp2, cspb1, mxi2. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
2.25Å     R-factor:   0.216     R-free:   0.249
Authors: C.Mohr,S.Jordan
Key ref: R.P.Wurz et al. (2009). Part 1: Structure-Activity Relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38alpha mitogen-activated protein kinase. Bioorg Med Chem Lett, 19, 4724-4728. PubMed id: 19574047 DOI: 10.1016/j.bmcl.2009.06.058
Date:
28-Aug-09     Release date:   02-Mar-10    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q16539  (MK14_HUMAN) -  Mitogen-activated protein kinase 14
Seq:
Struc:
360 a.a.
357 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 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!
  Cellular component     cell   8 terms 
  Biological process     intracellular signal transduction   70 terms 
  Biochemical function     nucleotide binding     11 terms  

 

 
    reference    
 
 
DOI no: 10.1016/j.bmcl.2009.06.058 Bioorg Med Chem Lett 19:4724-4728 (2009)
PubMed id: 19574047  
 
 
Part 1: Structure-Activity Relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38alpha mitogen-activated protein kinase.
R.P.Wurz, L.H.Pettus, S.Xu, B.Henkle, L.Sherman, M.Plant, K.Miner, H.McBride, L.M.Wong, C.J.Saris, M.R.Lee, S.Chmait, C.Mohr, F.Hsieh, A.S.Tasker.
 
  ABSTRACT  
 
A novel class of fused pyrazole-derived inhibitors of p38alpha mitogen-activated protein kinase (MAPK) is disclosed. These inhibitors were evaluated for their ability to inhibit the p38alpha enzyme, the secretion of TNFalpha in a LPS-challenged THP1 cell line and TNFalpha-induced production of IL-8 in 50% human whole blood. This series was optimized through a SAR investigation to provide inhibitors with IC(50) values in the low single-digit nanomolar range in whole blood. Further investigation of their pharmacokinetic profiles led to the identification of two potent and orally bioavailable p38 inhibitors 10 m and 10 q. Inhibitor 10 m was found to be efficacious in vivo in the inhibition of TNFalpha production in LPS-stimulated Lewis rats with an ED(50) of 0.1mg/kg while 10 q was found to have an ED(50) of 0.05-0.07 mg/kg.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20957100 P.Lan, Z.J.Huang, J.R.Sun, and W.M.Chen (2010).
3D-QSAR and Molecular Docking Studies on Fused Pyrazoles as p38α Mitogen-Activated Protein Kinase Inhibitors.
  Int J Mol Sci, 11, 3357-3374.  
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