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Update on Structure and Function of SH2 Domains: Mechanisms and Emerging Targeting Strategies
Moses M Kasembeli1, Jorge Rodas2, David J Tweardy1,3
1Department of Infectious Disease, Infection Control and Employee Health, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
International Journal of Molecular Sciences
|September 27, 2025
Summary
Protein phosphorylation regulates cellular processes by controlling protein interactions. This review focuses on phosphotyrosine recognition by SH2 domains and therapeutic strategies targeting these interactions.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Signaling
Background:
- Protein function is determined by its domains, regulated by post-translational modifications (PTMs).
- Phosphorylation, a reversible PTM, controls protein interactions and is vital for cellular processes like signaling, transcription, and metabolism.
- Phosphorylated proteins mediate extensive interaction networks, crucial for cellular regulation.
Purpose of the Study:
- To review structural insights into phosphotyrosine recognition by Src homology 2 (SH2) domains.
- To update approaches for targeting SH2 domains in drug discovery.
- To highlight inhibitors targeting SH2 domains that have advanced to clinical development.
Main Methods:
- Literature review focusing on structural biology and drug discovery.
- Analysis of mechanisms governing phosphotyrosine-ligand recognition by SH2 domains.
- Survey of inhibitors targeting SH2 domains in clinical development.
Main Results:
- SH2 domains specifically recognize phosphotyrosine (pY)-containing motifs, mediating critical signaling events.
- Structural insights reveal the molecular basis for SH2 domain-phosphopeptide interactions.
- Several SH2 domain inhibitors have progressed to clinical trials for various diseases.
Conclusions:
- Understanding SH2 domain-phosphotyrosine interactions is key to deciphering signaling pathways.
- Targeting SH2 domains offers a promising therapeutic strategy for diseases driven by aberrant signaling.
- Continued research in SH2 domain inhibition holds potential for novel drug development.
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