Targeting PTPN22 at Nonorthosteric Binding SitesA Fragment Approach

Area of Science:

• Biochemistry
• Immunology
• Pharmacology

Background:

• The protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is a critical negative regulator of T cell receptor signaling.
• A specific variant, PTPN22 (C1858T), shows associations with reduced cancer risk and improved survival in patients receiving anti-PD-L1 therapy, suggesting a role in tumor immunity.
• Targeting phosphatases is challenging due to conserved active sites, necessitating exploration of nonorthosteric binding sites.

Purpose of the Study:

• To develop a strategy for discovering and characterizing nonorthosteric ligands for the PTPN22 phosphatase domain.
• To identify novel small molecules that modulate PTPN22 activity through allosteric mechanisms.

Main Methods:

• A fragment screening approach was employed to identify potential ligands for PTPN22.
• A multidisciplinary characterization strategy was used, integrating experimental data with molecular dynamics simulations when cocrystallization failed.
• Ligand binding was confirmed at two previously unidentified nonorthosteric sites on the PTPN22 phosphatase domain.

Main Results:

• Identification and advancement of fragments that bind to PTPN22 at two novel nonorthosteric sites.
• Successful characterization of these ligands using an integrated experimental and computational approach.
• Demonstration of a viable strategy for targeting PTPN22 via nonorthosteric modulation.

Conclusions:

• The study successfully identified novel nonorthosteric binding sites and ligands for PTPN22.
• This approach provides a promising avenue for developing PTPN22-targeted therapeutics, potentially for cancer immunotherapy and autoimmune conditions.
• The findings highlight the potential of targeting allosteric sites in phosphatases, leveraging conserved structural features.