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Proteomic discovery and characterization of chemical tools that degrade the NuRD chromatin regulatory complex

降解 NuRD 染色质调控复合物的化学工具的蛋白质组学发现和表征

基本信息

批准号：
10324559
负责人：
David Ian Remillard
金额：
$ 5.05万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10324559
关键词：
Ablation Alkynes Architecture Behavior Biochemical CHD4 gene Case Study Cells Cellular biology Chemicals Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Co-Immunoprecipitations Complex Cysteine DNA Binding Deacetylase Dependence Development Disease Drug Design Drug Targeting Face Gene Expression Genes Genetic Genetic Transcription Goals HDAC1 gene Homeostasis Human Human Cell Line Individual Knock-out Laboratories Libraries Maps Mediating Medicine Modality Modification Mutagenesis NuRD complex Nucleosomes Pathway interactions Pharmacology Phenotype Process Proteins Proteomics Regulator Genes Research Role Site Specificity Suppressor-Effector T-Lymphocytes System T-Cell Activation T-Lymphocyte Transcription Process Transcription Regulatory Protein Transcriptional Regulation Triage Validation analog biological systems cell behavior cell type chemical group comparative design empowered gain of function gene therapy genetic regulatory protein improved insight loss of function member multicatalytic endopeptidase complex novel pleiotropism programs protein complex protein degradation response small molecule tool ubiquitin ligase virtual

项目摘要

Project Summary As virtually all aspects of cell behavior and identity converge upon programmed responses in gene expression, transcriptional control features centrally in both normal homeostasis and progression to disease. Accordingly, pharmacologic perturbation of gene regulatory machinery is an attractive approach for understanding and modulating complex cellular disease states. Transcriptionally targeted drugs must overcome key hurdles, however, including the limited accessibility of DNA binding factors and multi-component complexes to traditional drug design approaches, as well as the indiscriminate activity caused by disruption of transcriptional processes shared across distinct cell types and states. In this proposal, we present and build on a novel discovery of an immunosuppressive electrophilic chemical probe termed "L4" that avoids these pitfalls through its remarkable ability to cause selective degradation of multiple NuRD (Nucleosome Remodeling Deacetylase) complex subunits in a T-cell-restricted manner. Empowered by our laboratory’s recent development of chemical proteomic strategies to globally map small molecule-protein interactions in native biological systems, we propose a research strategy to study the mechanism of the unprecedented pharmacological features of L4 and their implications for broader drug design approaches to target transcriptional complexes. In addition, we will investigate the relationship between L4-mediated degradation of the NuRD complex and the compound’s blockade of T-cell activation. In Specific Aim 1, we will apply our group’s chemical proteomic expertise to characterize NuRD degradation by L4 and map relevant protein targets in human T-cells using a suite of L4- related compounds and NuRD complex-directed enrichment approaches. In Specific Aim 2, we will evaluate the role of candidate L4 targets underpinning NuRD degradation using genetic and biochemical approaches and examine how the identified mechanisms result in the striking features of multi-subunit degradation and state- dependent (cell type-restricted) activity. In Specific Aim 3, we extend to examine the relationship of L4’s action on NuRD to its ability to block T-cell activation, and assess and apply this compound as a tool for further study of T-cell biology. By providing in-depth understanding of the unique pharmacological activity of L4, the proposed research will contribute to the overarching goals of exploring both novel mechanisms in targeted protein degradation and state-dependent control of gene regulatory proteins. Together, these broader ambitions represent promising avenues to overcome challenges in the development of transcriptionally targeted chemical probes and medicines.

项目总结