Research Highlights
Molecular architecture of PTPN3-p38γ complex sheds light on structure-based drug design to antagonize Ras transformation

Ras signaling cascade has long been considered as an attractive therapeutic target for colorectal cancer (CRC) where PTPN3 is highly expressed and expected to promote Ras oncogenic signaling through dephosphorylation of fully activated p38γ. Recent attention has been drawn on the PDZ-mediated PTPN3-p38γ complex, which is known to be the novel target for Ras-dependent malignancies. However, the dynamic nature of the phosphatase-kinase interactions have so far resisted structural biologists to explore the detailed molecular insight of this important group of drug target.

Distinguished Research Fellow Dr. Andrew H.-J. Wang and Research Fellow Dr. Tzu-Ching Meng have determined PTPN3 in complex with mitogen-activated protein kinase 12 (MAPK12/p38γ) by a hybrid method combining X-ray crystallography, small-angle X-ray scattering (SAXS) and chemical cross-linking coupled with mass spectrometry (cross-linking/MS). The crystal structure presents a unique feature of the glutamic acid containing loop that defines the substrate specificity of PTPN3 towards fully activated p38γ. SAXS and cross-linking/MS were applied to probe the solution structure of PTPN3-p38γ active state complex. The research team further discovered that PTPN3 could form an intrinsic inhibitory conformation regulate by its PDZ domain in the absence of an appropriate substrate.

The findings of this research suggest two new directions for the rational drug design to target Ras transformation. First, an allosteric inhibitor can be designed to lock the PDZ and PTP domain so that PTPN3 may stay in its inhibitory conformation. Second, the novel inhibitory can be designed to suppress the interaction between the PDZ domain of PTPN3 and the PDZ binding motif of p38γ.

The complete article entitled: “Reciprocal allosteric regulation of p38γ and PTPN3 involves a PDZ domain-modulated complex formation” was published on Science Signaling, Oct 15, 2014.

Full articles available at: http://stke.sciencemag.org/content/7/347/ra98.abstract

Authors : Kai-En Chen, Shu-Yu Lin, Mei-Ju Wu, Meng-Ru Ho, Abirami Santhanam, Chia-Cheng Chou, Tzu-Ching Meng*, Andrew H.-J. Wang*

Updated : 2014.12.19