Protein N-terminal Methylation Mechanisms and Inhibition

本提案是R 01 GM 117675的竞争性更新申请，采用多学科方法， 增强我们对蛋白质α-N-末端甲基化的理解。α-N-末端甲基化起着重要的作用， 在调节细胞有丝分裂、染色质相互作用和DNA修复中起重要作用。其水平随着 细胞应激、衰老和发育过程的反应。α-N-末端的出现增加 典型X-P-K/R基序和非典型基序上的甲基化突出了这一点的重要性。 未充分探索的修改。然而，我们对这些基本问题的理解仍然存在重大差距。 生物过程。填补这些空白对于阐明α-N-末端甲基化介导的 的途径，并增加机会，设计新的治疗方法。的目的 研究是开发新的化学工具，并应用它们来了解介导的途径和功能。 蛋白质α-N-末端甲基化。同时，我们将阐明底物特异性的分子基础， 人甲基转移酶样13，其甲基化含有 在α-N-末端的新的GKEK基序。总的来说，我们相信这项研究工作具有巨大的意义。 有可能提供一个更清楚的了解机制和抑制NTMT，并阐明 蛋白质α-N-末端甲基化的生物学影响。完成拟议的工作将提供新的 化学工具，既为基础生物学研究，并有机会提高新的发展 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.