9QA5

Structure of the N-SH2 domain of SHP2 in complex with the phosphoY627-Gab1 (613-651) peptide

Summary for 9QA5

• Entry DOI: 10.2210/pdb9qa5/pdb
• Descriptor: Isoform 3 of Tyrosine-protein phosphatase non-receptor type 11, GRB2-associated-binding protein 1 (3 entities in total)
• Functional Keywords: sh2-domain, phosphatase, ptpn11, phospho-tyrosine, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 16230.06

Authors

Machner, L.,Breithaupt, C.,Kniest, J.,Parthier, C.,Feller, S.M.,Stubbs, M.T. (deposition date: 2025-02-27, release date: 2025-12-31, Last modification date: 2026-01-07)

Primary citation

Machner, L.,Shaikhqasem, A.,Gruber, T.,Hamdi, F.,Breithaupt, C.,Kniest, J.,Wiebe, F.,Lewitzky, M.,Parthier, C.,Kyrilis, F.L.,Balbach, J.,Kastritis, P.L.,Feller, S.M.,Stubbs, M.T.
Mechanism of SHP2 activation by bis-Tyr-phosphorylated Gab1.
Structure, 2025

PubMed Abstract: The non-receptor tyrosine phosphatase SHP2 (SH2 domain-containing protein tyrosine phosphatase 2) (PTPN11) is a regulator of diverse cellular functions including mitogenic activation and cell migration. It comprises two tandem Src-homology 2 (SH2) domains followed by the catalytic domain and is autoinhibited by the N-terminal SH2 domain blocking access to the active site. Mutations influencing auto-inhibition have been implicated in cancer and other diseases, and allosteric inhibitors have been developed that stabilize the inactive state. Here, we show that the intrinsically disordered bis-phosphorylated SHP2-activating peptide pYpY-Gab1 binds to both SH2 domains, undergoing partial ordering in the process. In addition to eliciting changes in SH2 domain dynamics, the peptide reorganizes their relative orientations to generate a new SH2-SH2 interface. Our data suggest an active conformation for SHP2 that is also applicable to the hematopoietic cell-specific SHP1 (PTPN6), shedding light on the activation mechanism of both enzymes and paving the way for the development of novel compounds to modulate SHP2 activity.

PubMed: 41435833
DOI: 10.1016/j.str.2025.11.018

Experimental method

X-RAY DIFFRACTION (2.08 Å)