PDBsum entry 4e6c

Transferase

PDB id: 4e6c

Contents

Protein chain

330 a.a.

Ligands

0O8

Waters ×73

PDB id:

4e6c

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, csbp, map kinase mxi2, max-interacting protein 2, mitogen-activated protein kinase p38 alpha, map kinase p38 alpha, stress-activated protein 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:

2.39Å 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

Date:

15-Mar-12 Release date: 31-Oct-12

Protein chain

Q16539  (MK14_HUMAN) -  Mitogen-activated protein kinase 14 from Homo sapiens

Seq: 360 a.a.

Struc: 330 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.11.24 - mitogen-activated protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

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.