Histone Modification Mechanisms and Inhibition

组蛋白修饰机制和抑制

• 批准号: 7937324
• 负责人: PHILIP A COLE
• 金额: $ 10万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937324
• 关键词: Acetyltransferase; Address; Binding; Biochemical; Biological; Biology; Catalysis; Catalytic Domain; Cells; Cellular Assay; Chemicals; Collaborations; Complex; Diabetes Mellitus; Disease; Disease model; E1A-associated p300 protein; EP300 gene; Endocrine System Diseases; Enzymes; Epigenetic Process; Explosion; Gene Expression; Gene Expression Regulation; Generations; Histone H3; Histone H4; Histones; Hydrazine; Hydrazines; Immune; Immune System Diseases; In Vitro; Indium; Intervention; Kinetics; Lead; Learning; Ligands; Ligation; Malignant Neoplasms; Memory; Molecular; Mutagenesis; Pathway interactions; Peptides; Pharmacology; Proteins; Proteomics; Regulation; Research; Roentgen Rays; Role; Screening procedure; Signal Transduction; Sorting - Cell Movement; Structure; Substrate Interaction; Suicide; Tail; Transcription Repressor/Corepressor; X-Ray Crystallography; Yang; analog; base; chromatin remodeling; histone acetyltransferase; histone modification; inhibitor/antagonist; insight; interest; methyl group; mutant; neuropsychiatry; novel; novel therapeutics; peptide analog; peptidomimetics; propargylamine; public health relevance; research study; scaffold; small molecule; synthetic peptide; therapeutic target; virtual

DESCRIPTION (provided by applicant): This application is a competing renewal application of GM62437 that concerns chemical approaches to sorting out the mechanisms, regulation, and functions of acetyltransferase and demethylase enzymes that modify histones and other proteins. p300/CBP histone acetyltransferase (HAT) and LSD1 histone demethylase are key enzymes that regulate gene expression and are potential therapeutic targets in a range of diseases. p300/CBP is a broadly acting HAT that has been implicated in modulating cancer pathways, endocrine disorders, immune signaling, and learning and memory. LSD1 is a transcriptional repressor that removes methyl groups from Lys4 of histone H3. In this application, we plan to build on our recent progress regarding structural analysis of the p300/CBP HAT domain and the LSD1 catalytic domain in complex with our synthetic inhibitors. There are four specific aims: 1) Determine the scope and mechanisms of p300/CBP HAT catalysis and regulation based on the p300 HAT X-ray structure. In this regard, we will investigate the role of the p300/CBP L1 loop and the autoregulatory loop using mutagensis and by employing expressed protein ligation. 2) Develop a new generation of selective small molecule HAT inhibitors and apply these to gene regulation and disease model studies. Virtual ligand screening will be employed based on the crystal structures of p300/CBP HAT and PCAF/GCN5 HAT in complex with bisubstrate analogs. 3) Determine the basis for LSD1 histone demethylase substrate recognition. Chemical and biochemical strategies will be used to discern the potential role of a substrate gamma turn. 4) Develop synthetic inhibitors for the modulation of LSD1 activity in cells and for use in proteomics analysis. Leads will be developed from propargylamine and hydrazine scaffolds. Taken together, these studies have the potential to uncover important insights into the basis of chromatin remodeling and define new directions for pharmacologic intervention. PUBLIC HEALTH RELEVANCE: There is increasing interest in the biology and pharmacology of epigenetics. This application addresses two key enzymes involved in the regulation of epigenetic chromatin remodeling. Insights obtained from this research plan could lead to new therapeutic strategies for cancer, diabetes, immune disorders, and neuropsychiatric conditions.

描述（由申请人提供）：本申请是GM 62437的竞争性更新申请，涉及化学方法来筛选修饰组蛋白和其他蛋白质的乙酰转移酶和脱甲基酶的机制、调节和功能。p300/CBP组蛋白乙酰转移酶（HAT）和LSD 1组蛋白去甲基化酶是调节基因表达的关键酶，是一系列疾病的潜在治疗靶点。p300/CBP是一种广泛作用的HAT，参与调节癌症途径、内分泌失调、免疫信号传导以及学习和记忆。LSD 1是一种转录抑制因子，可从组蛋白H3的Lys 4上去除甲基。在本申请中，我们计划建立在我们最近的进展，关于p300/CBP HAT结构域和LSD 1催化结构域与我们的合成抑制剂的复合物的结构分析。具体目标有四个：1）根据p300 HAT的X射线结构，确定p300/CBP HAT催化和调节的范围和机制。在这方面，我们将调查的作用，p300/CBP L1环和自动调节环使用诱变和采用表达蛋白连接。2)开发新一代选择性小分子HAT抑制剂，并将其应用于基因调控和疾病模型研究。将基于与双底物类似物复合的p300/CBP HAT和PCAF/GCN 5 HAT的晶体结构进行虚拟配体筛选。3)确定LSD 1组蛋白去甲基化酶底物识别的基础。化学和生物化学的策略将被用来辨别潜在的作用，基板伽马转。4)开发用于调节细胞中LSD 1活性和用于蛋白质组学分析的合成抑制剂。将从炔丙胺和肼支架开发电极导线。总之，这些研究有可能揭示染色质重塑基础的重要见解，并确定药物干预的新方向。公共卫生相关性：人们对表观遗传学的生物学和药理学越来越感兴趣。该申请涉及参与表观遗传染色质重塑调节的两种关键酶。从这项研究计划中获得的见解可能会导致癌症，糖尿病，免疫疾病和神经精神疾病的新治疗策略。