Understanding the roles of conformational constraints in functional phosphotyrosine mimics

该奖项将资助塔夫茨大学的Joshua Kritzer博士探索影响磷酸酪氨酸信号转导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是由磷酸酪氨酸介导的。虽然一些参与磷酸酪氨酸信号转导的蛋白质可以用小分子来抑制，但大多数都很难被化学家瞄准。在这个项目中，Kritzer小组将使用新的、结构复杂的分子来尝试在体外和活细胞中调节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了解。参与该项目的研究生和本科生还将参加小学工作坊，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以用来阻断酪氨酸激酶，但几乎没有对磷酸酪氨酸信号转导的其他成分，即SH2结构域和酪氨酸磷酸酶有用的抑制剂。传统的抑制这些蛋白质的方法使用磷酸酪氨酸异构体，它提高了亲和力，但代价是选择性低，细胞摄取能力差。相比之下，非磷酸化多肽中的连续限制产生了通过构象模拟磷酸酪氨酸的分子。这就产生了在亲和力、选择性、代谢稳定性和细胞摄取方面同时提高的抑制剂。小肽是SH2结构域和酪氨酸磷酸酶抑制剂的潜在来源，在细胞生物学的许多方面都有直接的应用。如果这些发现可以推广，就有可能利用这一策略针对一系列蛋白质-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.