Histone Modification Mechanisms and Inhibition

组蛋白修饰机制和抑制

基本信息

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
项目类别：
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

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

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项目摘要

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）：此申请是GM62437的竞争续订应用，该应用涉及化学方法来整理乙酰基转移酶和脱甲基酶的机制，调节和功能，从而修饰组蛋白和其他蛋白质。 P300/CBP组蛋白乙酰转移酶（HAT）和LSD1组蛋白脱甲基酶是调节基因表达的关键酶，并且是一系列疾病中潜在的治疗靶标。 P300/CBP是一个广泛的表演帽子，与调节癌症途径，内分泌疾病，免疫信号传导以及学习和记忆有关。 LSD1是一种转录阻遏物，可去除组蛋白H3的lys4甲基。在此应用程序中，我们计划基于对P300/CBP HAT结构域的结构分析以及与我们的合成抑制剂的复杂性的LSD1催化结构域的最新进展。有四个具体的目的：1）确定基于p300 HAT X射线结构的p300/CBP HAT催化和调节的范围和机制。在这方面，我们将使用诱变并使用表达的蛋白质连接来研究p300/cbp L1环和自动调节环的作用。 2）开发新一代的选择性小分子HAT抑制剂，并将其应用于基因调节和疾病模型研究。虚拟配体筛选将根据p300/cbp HAT和PCAF/GCN5 HAT的晶体结构进行使用，以与Bisubstrate类似物进行复合。 3）确定LSD1组蛋白脱甲基酶底物识别的基础。化学和生化策略将用于辨别基材伽马转弯的潜在作用。 4）开发用于调节细胞中LSD1活性并用于蛋白质组学分析的合成抑制剂。铅将从propgylamine和氢氮支架开发。综上所述，这些研究有可能发现重要的洞察力对染色质重塑的基础，并定义了用于药物干预的新方向。公共卫生相关性：对表观遗传学的生物学和药理学的兴趣越来越高。该应用程序解决了参与表观遗传染色质重塑调节的两个关键酶。从该研究计划中获得的见解可能会导致针对癌症，糖尿病，免疫疾病和神经精神疾病的新治疗策略。