Protein N-terminal Methylation Mechanisms and Inhibition

此提案是R01 GM117675的竞争性续订申请，它使用多学科方法来 增强我们对蛋白质α-N-末端甲基化的理解。α-N末端甲基化起到了 在调节细胞有丝分裂、染色质相互作用和DNA修复中的重要作用。它的级别增加为 对细胞应激、衰老和发育过程的反应。α-N-末端出现的次数越来越多 规范X-P-K/R基序和非规范基序上的甲基化突出了这一点的重要性 未被充分探索的修改。然而，在我们对这些基本原则理解上仍然存在很大差距 生物过程。填补这些空白对于阐明α-N末端甲基化是必不可少的 这是一种新的治疗途径，并增加了设计新的治疗方法的机会。这样做的目的是 研究是开发新的化学工具，并应用它们来理解介导的途径和功能 蛋白质α-N末端甲基化。同时，我们将阐明底物专一性的分子基础。 人甲基转移酶13甲基化真核细胞延伸因子1α，含有 在α-N末端有新的GKEK基序。综上所述，我们相信这项研究努力具有巨大的 有可能更清楚地了解非专利技术的机制和抑制，并揭示 蛋白质α-N末端甲基化的生物学影响。拟议工作的完成将提供新的 化学工具既为基础生物学研究提供了契机，又为新奇科技的发展提供了契机 靶向α-N末端甲基化相关通路的治疗方法。

This proposal is a competing renewal application of R01 GM117675 that uses a multidisciplinary approach to enhance our understanding of protein α-N-terminal methylation. The α-N-terminal methylation plays an essential role in regulating cell mitosis, chromatin interactions, and DNA repair. Its level is increased as response of cellular stress, aging, and developmental processes. The increasing occurrences of α-N-terminal methylation on the canonical X-P-K/R motif and noncanonical motifs highlight the importance of this underexplored modification. However, there are major gaps remain in our understanding of these fundamental biological processes. Filling these gaps is essential to elucidate the α-N-terminal methylation-mediated pathways and to enhance the opportunity to devise novel therapeutic approaches. The objective of this research is to develop novel chemical tools and apply them to understand the pathway and functions mediated protein α-N-terminal methylation. Meanwhile, we will elucidate the molecular basis for substrate specificity of human methyltransferase like 13 that methylates the the eukaryotic elongation factor 1 alpha containing the new GKEK motif at the α-N-terminus. Taken together, we believe that this research effort has the great potential to provide a clearer understanding of mechanisms and inhibition of NTMTs, and shed lights on the biological impact of protein α-N-terminal methylation. Accomplishment of the proposed work will provide new chemical tools for both basic biology research and has the opportunity to enhance the development of novel therapeutic approaches to target α-N-terminal methylation-involved pathways.