PDBsum entry 4qun

Hydrolase

PDB id: 4qun

Contents

Protein chains

283 a.a.

Ligands

PO4 ×2

GOL

Waters ×338

References listed in PDB file

Key reference

• Title: Reciprocal allosteric regulation of p38γ and ptpn3 involves a pdz domain-Modulated complex formation.
• Authors: K.E.Chen, S.Y.Lin, M.J.Wu, M.R.Ho, A.Santhanam, C.C.Chou, T.C.Meng, A.H.Wang.
• Ref.: Sci Signal, 2014, 7, ra98. [DOI no: 10.1126/scisignal.2005722]
• PubMed id: 25314968

Abstract

The mitogen-activated protein kinase p38γ (also known as MAPK12) and its specific phosphatase PTPN3 (also known as PTPH1) cooperate to promote Ras-induced oncogenesis. We determined the architecture of the PTPN3-p38γ complex by a hybrid method combining x-ray crystallography, small-angle x-ray scattering, and chemical cross-linking coupled to mass spectrometry. A unique feature of the glutamic acid-containing loop (E-loop) of the phosphatase domain defined the substrate specificity of PTPN3 toward fully activated p38γ. The solution structure revealed the formation of an active-state complex between p38γ and the phosphatase domain of PTPN3. The PDZ domain of PTPN3 stabilized the active-state complex through an interaction with the PDZ-binding motif of p38γ. This interaction alleviated autoinhibition of PTPN3, enabling efficient tyrosine dephosphorylation of p38γ. Our findings may enable structure-based drug design targeting the PTPN3-p38γ interaction as an anticancer therapeutic.