Understanding the roles of conformational constraints in functional phosphotyrosine mimics

有了这个奖项，化学部的生命过程化学项目资助塔夫茨大学的约书亚克里泽博士探索影响磷酸酪氨酸信号的分子的结构和功能。 在所有高等生物中，细胞生长和功能的重要信号都是由磷酸酪氨酸介导的。 虽然一些参与磷酸酪氨酸信号传导的蛋白质可以用小分子抑制，但大多数蛋白质对化学家来说很难靶向。 在这个项目中，Kritzer小组将使用新的结构复杂的分子来尝试调节体外和活细胞中磷酸酪氨酸信号蛋白的活性。 了解这些分子的结构和功能有望提高我们设计具有有用功能的分子的能力，以及我们对这些分子如何与生命系统相互作用的知识。 参与该项目的研究生和本科生还将参加小学讲习班，重点是教授使用微生物的科学方法。 虽然有许多有用的和选择性的抑制剂可用于阻断酪氨酸激酶，但几乎没有有用的抑制剂用于磷酸酪氨酸信号传导的其他组分，即SH 2结构域和酪氨酸磷酸酶。 抑制这些蛋白质的传统方法使用磷酸酪氨酸电子等排体，其以低选择性和差的细胞摄取为代价提高亲和力。 相比之下，非磷酸化肽内的连续约束通过其构象产生模拟磷酸酪氨酸的分子。 这产生了同时改善亲和力、选择性、代谢稳定性和细胞摄取的抑制剂。 小的，高度约束的肽是一个有前途的来源抑制剂的SH 2结构域和酪氨酸磷酸酶，这将有直接的应用在细胞生物学的许多方面。 如果这些发现可以推广，那么有可能用这种策略靶向一系列蛋白质-蛋白质相互作用。

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Joshua Kritzer of Tufts University to explore the structures and functions of molecules that affect phosphotyrosine signaling. In all higher organisms, important signals for cell growth and function are mediated by phosphotyrosine. While some of the proteins involved in phosphotyrosine signaling can be inhibited using small molecules, most are difficult for chemists to target. In this project, the Kritzer group will use new, structurally complex molecules to attempt to modulate the activity of phosphotyrosine-signaling proteins in vitro and in living cells. Understanding the structures and functions of these molecules is expected to advance our ability to design molecules with useful function, and our knowledge of how such molecules interact with living systems. Graduate students and undergraduates participating in this project will also participate in grade school workshops focused on teaching the scientific method using microbes. While there are many useful and selective inhibitors available for blocking tyrosine kinases, there are almost no useful inhibitors for the other components of phosphotyrosine signaling, namely SH2 domains and tyrosine phosphatases. Traditional approaches to inhibiting these proteins use phosphotyrosine isosteres, which improve affinity at the cost of low selectivity and poor cell uptake. By contrast, successive constraints within a non-phosphorylated peptide produce molecules that mimic phosphotyrosine via their conformation. This produces inhibitors with simultaneous improvements in affinity, selectivity, metabolic stability, and cellular uptake. Small, highly constrained peptides are a promising source for inhibitors of SH2 domains and tyrosine phosphatases, which would have direct applications in many aspects of cell biology. If the findings can be generalized, it may be possible to target a range of protein-protein interactions with this strategy.