Protein N-terminal Methylation Mechanisms and Inhibition

蛋白质 N 末端甲基化机制和抑制

• 批准号: 10592404
• 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/10592404
• 关键词: ATP phosphohydrolase; Affect; Aging; Arginine; Biological; Biological Process; Biology; Carbamates; Cells; Cellular Stress; Ceramide glucosyltransferase; Chemicals; Chromatin; Chromosome Condensation; Complex; 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; Ligation; 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的竞争性更新申请，使用多学科方法