Abstract
Protein tyrosine phosphatases (PTPs) are important therapeutic targets for a range of human pathologies. However, the common architecture of PTP active sites impedes the discovery of selective PTP inhibitors. Our laboratory has recently developed methods to inhibit PTPs allosterically by targeting cysteine residues that either (i) are not conserved in the PTP family or (ii) result from pathogenic mutations. Here, we describe screening protocols for the identification of selective inhibitors that covalently engage such “rare” cysteines in target PTPs. Moreover, to elucidate the breadth of possible applications of our cysteine-directed screening protocols, we provide a brief overview of the nonconserved cysteines present in all human classical PTP domains.
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Acknowledgments
The authors thank Rachel Seifert for bioinformatic analysis of nonconserved cysteines in PTP domains and HyoJeon Kim and Lynn Kao for help in the development of compound-screening protocols. Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R15GM071388. Funding from Amherst College is also gratefully acknowledged.
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Bishop, A.C., Serbina, A. (2024). Targeting Nonconserved and Pathogenic Cysteines of Protein Tyrosine Phosphatases with Small Molecules. In: Thévenin, D., P. Müller, J. (eds) Protein Tyrosine Phosphatases. Methods in Molecular Biology, vol 2743. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-3569-8_17
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DOI: https://doi.org/10.1007/978-1-0716-3569-8_17
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