Protein tyrosine phosphatases (PTPs), which catalyze the dephosphorylation of protein substrates and function in many signaling pathways, have been extensively implicated in disease, and have emerged as promising targets for therapeutic drug discovery. Because the catalytic domains of many PTPs are largely conserved, and because active-site-directed pharmacophores are generally negatively charged, selective and bioavailable active-site inhibitors have been difficult to find. Allosteric inhibition is not limited by these challenges, so discovering new PTP allosteric sites that can be targeted for enzyme inhibition is particularly valuable. Building on precedents that have shown that non-conserved cysteine residues can be targeted for selective inhibition in other protein families, we have systematically located all of the non-conserved cysteines in the classical PTP family to identify potential allosteric inhibition sites. In order to test whether targeting these identified non-conserved cysteine residues affects enzymatic activity, we engineered cysteine-rich motifs around cysteines of interest to which biarsenical small molecules can selectively and potently bind. Measuring the activity of these biarsenical-bound PTPs as compared to the wild-type PTP allows us to evaluate whether specific non-conserved cysteine residues are located in allosteric inhibition sites that could potentially be targeted in disease-causing PTPs for therapeutic inhibition.

Systematic identification of allosteric inhibition sites on protein tyrosine phosphatases

2019 Fall National Meeting

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