Protein tyrosine phosphatase inactivation by electrophilic tyrosine modification

Chemical Science 2026 Open access

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Authors: Madeleine L. Ware, David M. Leace, Zihan Qu, Quentin Schaefer, Sagar D. Vaidya, Mikayla L. Horvath, Zhihong Li, Yunpeng Bai, Zhong-Yin Zhang, Ku‐Lung Hsu
DOI: 10.1039/d5sc07398g
Cited by: 2
References: 41

Abstract

a ligand induced protein tethering (LIPT) mechanism. We detected ligand binding at Y279, which is in proximity to the catalytic cysteine on SHP2 and has known functional and pathogenic properties. Covalent SHP2 modification by DML189 induced reversible disulfide tethering and monomer loss that was not observed to the same extent on PTP1B, LYP, or SHP1. Crosslinking mass spectrometry detected unique tethering events involving regulatory cysteines after DML189 modification on SHP2. Together, we discovered a tyrosine reactive inhibitor that targets functional sites on SHP2 and exhibits molecular glue activity through LIPT.

Fields of Study & Subjects

Protein Tyrosine Phosphatases Diabetes and associated disorders Microbial metabolism and enzyme function

Publication details

Journal / source
Chemical Science
Publisher
Royal Society of Chemistry (RSC)
Volume
17
Issue
10
Pages
5163–5171
Publication date
1 January 2026
Language
EN