9QCD

Micro-ED structure of the NSH2-CSH2 tandem domain of SHP2 in complex with the bis-phosphorylated pY627-pY659-Gab1 (613-694) peptide

9QCD の概要

• エントリーDOI: 10.2210/pdb9qcd/pdb
• 分子名称: Tyrosine-protein phosphatase non-receptor type 11, GRB2-associated-binding protein 1 (2 entities in total)
• 機能のキーワード: sh2-domain, phosphatase, ptpn11, phospho-tyrosine, signaling protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 32840.52

構造登録者

Machner, L.,Shaikhqasem, A.,Hamdi, F.,Breithaupt, C.,Parthier, C.,Kyrilis, F.L.,Kastritis, P.L.,Feller, S.M.,Stubbs, M.T. (登録日: 2025-03-04, 公開日: 2025-12-31, 最終更新日: 2026-03-18)

主引用文献

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, 34:441-453.e7, 2026

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

実験手法

ELECTRON CRYSTALLOGRAPHY (3.2 Å)