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Protein tyrosine phosphatases (PTPs) are signaling enzymes that play a key role in regulating a broad range of biological pathways. Following recent biochemical studies and through new drug development techniques, PTPs have been indicated as prospects for drug discovery. Src homology 2 containing phosphatase 1 (SHP-1) is a cytosolic PTP with the ability to inhibit a number of pathways which enhance macrophage and T cell function. Thus, blocking SHP-1 activity is anticipated to magnify innate and adaptive immunity against tumor cells, characterizing SHP-1 as a novel target for cancer immunotherapy. One small molecule drug that has displayed promise for its ability to inhibit SHP-1 is M029, however, no structure of this complex has been reported. The goal of this project is to obtain a detailed visualization of such a structure in hopes of providing a more direct approach to fully understanding the nature of interactions between SHP-1 and M029. In this study, nickel-affinity purification and size exclusion chromatography were used for the purification of SHP-1. Subsequently, crystals of SHP-1 were soaked with M029 for X-ray diffraction experiments. Data were collected from these crystals and is currently being processed for structure determination. Additionally, the SHP-1 expression construct is undergoing further optimization to increase compactness and improve crystallization screening. Crystal soaks and co-crystallization will then be performed using the new construct. Since preliminary data suggests M029 as a potential contributor to anti-cancer immunity, solving the SHP- 1/M029 complex structure will provide direct evidence for the potency and selectivity of M029 binding.

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Purdue University / 2023

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Am Author