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PDBsum entry 4e8a

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protein ligands links
Transferase PDB id
4e8a
Jmol
Contents
Protein chain
327 a.a.
Ligands
0OA
Waters ×9
PDB id:
4e8a
Name: Transferase
Title: The crystal structure of p38a map kinase in complex with pia
Structure: Mitogen-activated protein kinase 14. Chain: a. Synonym: map kinase 14, mapk 14, cytokine suppressive anti- inflammatory drug-binding protein, csaid-binding protein, c kinase mxi2, max-interacting protein 2, mitogen-activated p kinase p38 alpha, map kinase p38 alpha, stress-activated pr kinase 2a, sapk2a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: mapk14, csbp, csbp1, csbp2, cspb1, mxi2, sapk2a. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.70Å     R-factor:   0.225     R-free:   0.313
Authors: O.Livnah,N.Tzarum,Y Eisenberg-Domovich
Key ref: N.Tzarum et al. (2012). Lipid molecules induce p38α activation via a novel molecular switch. J Mol Biol, 424, 339-353. PubMed id: 23079240 DOI: 10.1016/j.jmb.2012.10.007
Date:
20-Mar-12     Release date:   31-Oct-12    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q16539  (MK14_HUMAN) -  Mitogen-activated protein kinase 14
Seq:
Struc:
360 a.a.
327 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   71 terms 
  Biochemical function     nucleotide binding     11 terms  

 

 
    reference    
 
 
DOI no: 10.1016/j.jmb.2012.10.007 J Mol Biol 424:339-353 (2012)
PubMed id: 23079240  
 
 
Lipid molecules induce p38α activation via a novel molecular switch.
N.Tzarum, Y.Eisenberg-Domovich, J.J.Gills, P.A.Dennis, O.Livnah.
 
  ABSTRACT  
 
p38α mitogen-activated protein kinase (MAPK) is generally activated by dual phosphorylation but has also been shown to exhibit alternative activation modes. One of these modes included a direct interaction with phosphatidylinositol ether lipid analogues (PIA) inducing p38α autoactivation and apoptosis. Perifosine, an Akt inhibitor in phase II clinical trials, also showed p38α activation properties similarly to those of PIAs. The crystal structures of p38α in complex with PIA23, PIA24 and perifosine provide insights into this unique activation mode. The activating molecules bind a unique hydrophobic binding site in the kinase C'-lobe formed in part by the MAPK insert region. In addition, there are conformational changes in the short αEF/αF loop region that acts as an activation switch, inducing autophosphorylation. Structural and biochemical characterization of the αEF/αF loop identified Trp197 as a key residue in the lipid binding and in p38α catalytic activity. The lipid binding site also accommodates hydrophobic inhibitor molecules and, thus, can serve as a novel p38α-target for specific activation or inhibition, with novel therapeutic implications.