4QUM

Crystal structure of PTPN3 (PTPH1) in complex with a dually phosphorylated MAPK12 peptide

Summary for 4QUM

• Entry DOI: 10.2210/pdb4qum/pdb
• Related: 1CM8 2B49 4QUN
• Descriptor: Tyrosine-protein phosphatase non-receptor type 3, Mitogen-activated protein kinase 12 (3 entities in total)
• Functional Keywords: alpha beta, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 36131.92

Authors

Chen, K.E.,Meng, T.C.,Wang, A.H.J. (deposition date: 2014-07-10, release date: 2014-12-10, Last modification date: 2024-11-13)

Primary citation

Chen, K.E.,Lin, S.Y.,Wu, M.J.,Ho, M.R.,Santhanam, A.,Chou, C.C.,Meng, T.C.,Wang, A.H.J.
Reciprocal allosteric regulation of p38 gamma and PTPN3 involves a PDZ domain-modulated complex formation.
Sci.Signal., 7:ra98-ra98, 2014

PubMed 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.

PubMed: 25314968
DOI: 10.1126/scisignal.2005722

Experimental method

X-RAY DIFFRACTION (2.516 Å)