9YDM

Targeting PTPN22 at non-orthosteric binding sites - a fragment approach

This is a non-PDB format compatible entry.

Summary for 9YDM

• Entry DOI: 10.2210/pdb9ydm/pdb
• Descriptor: Tyrosine-protein phosphatase non-receptor type 22, ETHANOL, GLYCEROL, ... (6 entities in total)
• Functional Keywords: non-receptor protein tyrosine phosphatase, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 76617.36

Authors

Di Lello, P.,Wells, M.M. (deposition date: 2025-09-22, release date: 2026-01-28, Last modification date: 2026-02-11)

Primary citation

Di Lello, P.,Wells, M.M.,Davis, B.,Daniels, Z.,Garner, T.P.,Gazzard, L.,Harris, R.,Hubbard, R.E.,Landry, M.L.,Martin, B.,Morgan, J.L.W.,Patapoff, A.,Simmonite, H.,Skelton, N.,Ultsch, M.,Walters, B.T.,Wu, P.,Dimitrova, Y.N.,Huard, K.
Targeting PTPN22 at Nonorthosteric Binding SitesA Fragment Approach.
Acs Omega, 11:3465-3480, 2026

PubMed Abstract: Nonreceptor protein tyrosine phosphatase 22 (PTPN22) is a known negative regulator of T cell receptor signaling. PTPN22's pro-autoimmune variant (C1858T) was found to have a risk preventive association with multiple types of cancer, to contribute to improved overall survival in patients treated with the anti-PD-L1 atezolizumab, and to enhance tumor immunity in mice. Modulating the activity of phosphatases has been historically challenging due to the polar and conserved nature of the orthosteric sites across the protein family. In this work, we outline a strategy for discovering and characterizing nonorthosteric ligands of the PTPN22 phosphatase domain. We opted for a fragment screen to identify ligands of PTPN22 and utilized a multidisciplinary approach to characterize them. This included the integration of experimental data-driven molecular dynamics when cocrystallization of fragments with PTPN22 was unsuccessful. With this approach, we identified and advanced fragments that bind PTPN22 at two novel nonorthosteric sites. Due to the shared tertiary structure of the phosphatase domain, we believe this hit finding effort, combined with knowledge about the allosteric circuitry of phosphatases, can provide synergistic value.

PubMed: 41585704
DOI: 10.1021/acsomega.5c11028

Experimental method

X-RAY DIFFRACTION (1.99 Å)