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Updated: Jun 13, 2026
08:45
Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors
Published on: July 17, 2020
Loops govern SH2 domain specificity by controlling access to binding pockets.
Tomonori Kaneko1, Haiming Huang, Bing Zhao
1Department of Biochemistry and the Siebens-Drake Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5C1.
Science Signaling
|May 6, 2010
Summary
Surface loops in Src homology 2 (SH2) domains control binding pocket access, enabling selective recognition of phosphotyrosine motifs. This structural insight provides a basis for engineering SH2 domains and designing specific inhibitors.
Area of Science:
- Molecular Biology
- Structural Biology
- Biochemistry
Background:
- Cellular functions rely on protein-protein interactions mediated by modular domains.
- Understanding how different domain family members select distinct sequence motifs is crucial.
- Human Src homology 2 (SH2) domains (120 in 110 proteins) bind phosphotyrosine (pTyr)-containing sequences.
Purpose of the Study:
- Investigate the molecular basis of sequence motif selection by SH2 domains.
- Determine the role of binding pockets and surface loops in SH2 domain specificity.
- Provide a framework for engineering SH2 domains and designing inhibitors.
Main Methods:
- Structural analysis of 63 SH2 domain structures, including the BRDG1 SH2 domain.
- Identification of conserved structural features in SH2 domain loops.
- Engineering of SH2 domain loops to alter binding specificity.
Main Results:
- SH2 domains possess three binding pockets selective for positions after pTyr.
- Surface loops dictate pocket accessibility and shape, controlling ligand recognition.
- Conserved loop features regulate access to binding pockets despite sequence variability.
- Engineered loops successfully altered SH2 domain specificity as predicted.
Conclusions:
- Selective blockage of binding pockets by surface loops explains diverse SH2 domain ligand recognition.
- This provides a molecular basis for the evolution of SH2 domain specificity.
- Offers a framework for engineering SH2 domains and developing targeted inhibitors.
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