4E5A

The W197A mutant of p38a MAP kinase

Summary for 4E5A

• Entry DOI: 10.2210/pdb4e5a/pdb
• Related: 1P38 2NPQ 4E5B 4E6A 4E6C 4E8A
• Descriptor: Mitogen-activated protein kinase 14 (2 entities in total)
• Functional Keywords: map kinase, p38, signal trunsduction, alternative activation modes, kinase tompoly, kinase, phosphorylaiton, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : Q16539
• Total number of polymer chains: 1
• Total formula weight: 41228.07

Authors

Livnah, O.,Tzarum, N.,Eisenberg-Domovich, Y. (deposition date: 2012-03-14, release date: 2012-10-31, Last modification date: 2024-02-28)

Primary citation

Tzarum, N.,Eisenberg-Domovich, Y.,Gills, J.J.,Dennis, P.A.,Livnah, O.
Lipid Molecules Induce p38 alpha Activation via a Novel Molecular Switch.
J.Mol.Biol., 424:339-353, 2012

PubMed 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.

PubMed: 23079240
DOI: 10.1016/j.jmb.2012.10.007

Experimental method

X-RAY DIFFRACTION (1.87 Å)