Department of Chemistry, Amherst College, Amherst, MA, USA.
Methods Mol Biol. 2024;2743:271-283. doi: 10.1007/978-1-0716-3569-8_17.
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.
蛋白质酪氨酸磷酸酶（PTPs）是多种人类病理的重要治疗靶点。然而，PTP 活性位点的常见结构阻碍了选择性 PTP 抑制剂的发现。我们实验室最近开发了通过靶向在 PTP 家族中不保守或源自致病性突变的半胱氨酸残基来别构抑制 PTP 的方法。在这里，我们描述了用于鉴定选择性抑制剂的筛选方案，这些抑制剂可与靶 PTP 中的此类“稀有”半胱氨酸发生共价结合。此外，为了阐明我们针对半胱氨酸的筛选方案可能的应用范围，我们简要概述了所有人类经典 PTP 结构域中存在的非保守半胱氨酸。
