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Profile substrates and inhibitors of protein lysine methyltransferase

蛋白质赖氨酸甲基转移酶的底物和抑制剂概况

基本信息

批准号：
8964372
负责人：
Minkui Luo
金额：
$ 47.05万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8964372
关键词：
Binding Binding Sites Bioinformatics Biological Biological Process Biology Cells Chemicals Collection Complex Computer Simulation Data Dependence Disease Dose Engineering Enzymes Epigenetic Process Event Family Genetic Transcription Goals Histone-Lysine N-Methyltransferase Human Genome In Vitro Individual Label Laboratories Lead Life Light Malignant Neoplasms Mediating Methionine Methods Methylation Methyltransferase Outcome Pathway interactions Pattern Pharmaceutical Chemistry Phosphorylation Post-Translational Protein Processing Protein Isoforms Protein Methylation Protein Methyltransferases Protein Microchips Protein-Arginine N-Methyltransferase RNA Splicing Reagent Recombinant Proteins Research Role Stem cells Technology Therapeutic Therapeutic Intervention Transcriptional Regulation Work X-Ray Crystallography analog arginyllysine base cancer stem cell cancer type cell type coactivator-associated arginine methyltransferase 1 cofactor disease diagnosis flexibility inhibitor/antagonist innovation new therapeutic target public health relevance scaffold simulation sinefungin

项目摘要

DESCRIPTION (provided by applicant): Numerous biological events need to be orchestrated at an epigenetic level upon defining cellular fate. Among the key epigenetic regulators are protein methyltransferases (PMTs), which methylate specific Arg/Lys residues with S-adenosyl-L- methionine (SAM) as a cofactor. Whereas many recombinant PMTs are active in vitro, their cellular activities can largely depend on the presence of distinct PMT isoforms or complexes. Such context- dependent complexity makes it challenging to solely rely on conventional methods to elucidate the targets of PMTs. The flexible substrate-recognizing patterns of PMTs, together with their highly- conserved SAM-binding motifs, also made it challenging to develop PMT inhibitors with potency and selectivity. A long-term goal of the project is to elucidate and manipulate methyltransferase- involved epigenetic for disease diagnosis and treatments. The objective of this application is to use SAM mimics as probes to profile cell-type-specific substrates of PMTs and to perturb PMTs in a specific manner. Here an integrative Bioorthogonal Profiling of Protein Methylation (BPPM) will be implemented to dissect the substrates of designated PMTs in relevant biological contexts. A subtype of methylation events associated with specific biological processes will be further validated with well-established methods. Their functional roles will be examined in the context of cancer malignancy or stem cell reprogramming. In parallel, stable SAM analogues will be pursued as target-specific inhibitors against PMTs. The completion of this proposal will unambiguously reveal the substrates of multiple PMTs and characterize high-quality PMT inhibitors in relevant cellular contexts. The impact of these substrate-profiling and inhibitor-identifying strategies further lie n their general applicability to other methyltransferases.