Protein Tyrosine Phosphatase 1B (PTP1B) is the archetypal member of the PTP family and a validated target for a number of diseases including diabetes and cancer. The conserved active sites of PTPs are highly polar and present challenges for the development of specific and bioavailable small-molecule modulators. Allosteric sites on proteins have long been understood to be of potential use in the development of specific targeted therapeutics, but the mechanisms that convey a signal through a protein’s structure remain poorly understood. A recently identified L16 allosteric site  in PTP1B is of particular interest because of its lack of conservation amongst the PTPs. To explore the allosteric potential of the L16 site, we have used biophysical experiments to characterize the structural and functional effects of new compounds that were designed to target this site using the Atomwise AtomNet artificial intelligence system applied to crystal structures from a previous fragment soaking screen of PTP1B. Among the top predicted compounds, we have identified both high-affinity but benign  binders, and  inhibitors.  The structural and dynamical changes these compounds brought about in PTP1B were further analyzed using hydrogen-deuterium exchange mass spectrometry (HDX-MS) and X-ray crystallography. Despite being targeted to the same L16 binding pocket, these ligands induce distinct structural and dynamical responses in PTP1B, suggesting that the two inhibitors may involve different loci in PTP1B’s structure in conveying their modulation. Overall, this work provides promising new allosteric footholds for the long-studied therapeutic target PTP1B.

Structural and dynamical responses to small-molecule inhibitors targeting a new allosteric site in PTP1B

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ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.