PDBsum entry 4e6c

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protein ligands links
Transferase PDB id
Protein chain
330 a.a.
Waters ×73
PDB id:
Name: Transferase
Title: P38a-perifosine complex
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.
2.39Å     R-factor:   0.217     R-free:   0.292
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
15-Mar-12     Release date:   31-Oct-12    
Go to PROCHECK summary

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

 Enzyme reactions 
   Enzyme class: E.C.  - Mitogen-activated protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
+ protein
+ 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  


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.
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.