Peptides and Small-molecules Targeting Signaling Proteins and Protein-Protein Interfaces

细胞表面受体和细胞内调节蛋白是细胞内 这些蛋白参与了一系列的相互作用和信号传导。因此， 它们信号周期的不同阶段为治疗干预提供了独特的机会。 该项目提供了与实验数据相结合的计算研究，以解决 新型多肽模拟物及其类似物细胞外靶向识别机制研究 胰岛素家族受体蛋白结构域与细胞内靶向小分子 G蛋白偶联受体调节蛋白中的蛋白质相互作用 一家人。拟议的研究是及时的，因为最近的几项结构研究揭示了 天然激素胰岛素和同源生长因子多肽与WE的结合方式 开发了基于动力学的计算方法，为 设计基于多肽的新型激动剂和拮抗剂。朝着这个方向发展的是我们的 建议研究的三类多肽：(1)合成胰岛素模拟物，(2)病毒胰岛素样 从锥形蜗牛毒液中提取的多肽(VILP)和胰岛素样多肽。我们的第二项研究 Direction的目标是开发针对关键细胞内蛋白质-蛋白质的小分子抑制剂 G-蛋白信号转导调节蛋白(RGS)与α-亚基的相互作用 G蛋白。与直接以蛋白质-蛋白质为靶点的传统方法相反 界面，我们建议以RGS蛋白上的变构为靶点来抑制蛋白质-蛋白质 互动。通过对一种模型蛋白质的初步研究，我们发现变构 控制和定向是可行的，通过这个项目，我们建议扩大 这些有希望的研究涉及癌症和视觉信号中的新蛋白质靶点。总的来说， 我们预计，从这些研究中出现的机械论范式将有更广泛的 对其他蛋白质家族的适用性，并将有助于设计新的治疗策略。

Cell-surface receptors and intracellular regulatory proteins are preeminent mediators of cellular signaling as these proteins are involved in a host of interactions and pathways. Therefore, various stages of their signaling cycles provide unique opportunities for therapeutic intervention. This project presents computational studies integrated with experimental data to resolve the mechanisms of recognition of novel peptide mimetics and analogues targeting extracellular domains of receptor proteins of the insulin family and small-molecules targeting intracellular protein-protein interactions in regulatory proteins of the G-protein coupled receptor (GPCR) family. The proposed studies are timely in that several recent structural studies have revealed the binding modes of the native hormone insulin and homologous growth factor peptides and we have developed dynamics-based computational approaches that have opened the avenues for designing novel peptide-based agonists and antagonists. Toward this direction are our proposed studies of three classes of peptides: (1) synthetic insulin mimetics, (2) viral-insulin-like peptides (VILPs), and insulin-like peptides from cone snail venom. Our second research direction aims to develop small-molecule inhibitors targeting a key intracellular protein-protein interaction between regulators of G-protein signaling (RGS) proteins and the alpha-subunits of G-proteins. As opposed to the conventional approach of directly targeting the protein-protein interface, we propose to target allosteric sites on RGS proteins to inhibit the protein-protein interaction. Through preliminary studies on a model protein, we have shown that allosteric control and targeting is feasible and through this project we propose to broaden the scope of these promising studies to new protein targets involved in cancer and visual signaling. Overall, we anticipate that the mechanistic paradigms emerging from these studies will have broader applicability to other protein families and will facilitate the design of novel therapeutic strategies.