Protein N-terminal Methylation Mechanisms and Inhibition

蛋白质 N 末端甲基化机制和抑制

• 批准号: 10446478
• 负责人: Rong Huang
• 金额: $ 30.77万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-20 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446478
• 关键词: ATP phosphohydrolase; Affect; Aging; Arginine; Biological; Biological Process; Biology; Carbamates; Cells; Cellular Stress Response; Ceramide glucosyltransferase; Chemicals; Chromatin; Chromosome Condensation; Complex; Crystallization; DNA Damage; DNA Repair; DNA-Binding Proteins; Data; Defect; Development; Developmental Process; Disease; Goals; Guanosine Triphosphate Phosphohydrolases; Histones; Human; Kinetics; Knock-out; Knockout Mice; Knowledge; Lead; Ligation; Light; Lysine; Malignant Neoplasms; Mediating; Methylation; Methyltransferase; Mitosis; Modification; Molecular; Molecular Chaperones; Myosin Alkali Light Chains; N-terminal; Oncoproteins; Pathway interactions; Peptide Elongation Factor 1; Peptides; Phenotype; Play; Poly(ADP-ribose) Polymerases; Premature aging syndrome; Protein phosphatase; Proteins; Proteomics; Quinuclidines; Reporting; Research; Retinoblastoma; Roentgen Rays; Role; Series; Specificity; Speed; Structure; Substrate Specificity; Therapeutic; Translations; Up-Regulation; Work; analog; centromere protein A; experience; high throughput screening; human disease; improved; infancy; inhibitor; interdisciplinary approach; novel; novel therapeutic intervention; programs; protein function; public health relevance; small molecule inhibitor; success; template activating factor-I; tool; transcriptomics; tumorigenesis

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.

该提案是 R01 GM117675 的竞争性续展申请，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作用。 在调节细胞有丝分裂、染色质相互作用和 DNA 修复中发挥重要作用。 细胞应激、衰老和发育过程的反应 α-N-末端的出现增加。 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 然而，我们对这些基本原理的理解仍然存在重大差距。 填补这些空白对于阐明 α-N 末端甲基化介导至关重要。 途径并增加设计新治疗方法的机会。 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 同时，我们将阐明蛋白质α-N-末端甲基化的底物特异性的分子基础。 人类甲基转移酶如 13，使真核延伸因子 1 α 甲基化，其中含有 总而言之，我们相信这项研究工作具有巨大的意义。 有望更清楚地了解 NTMT 的机制和抑制，并阐明 蛋白质α-N-末端甲基化的生物学影响的完成将提供新的建议工作。 用于基础生物学研究的化学工具，并有机会促进新型药物的开发 针对 α-N 末端甲基化相关途径的治疗方法。