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Mechanistic studies of corepressor-mediated PPARγ transcriptional repression

辅阻遏物介导的 PPARγ 转录抑制的机制研究

基本信息

批准号：
10830181
负责人：
Douglas Kojetin
金额：
$ 36.86万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10830181
关键词：
Mechanistic studies corepressor mediated PPAR

项目摘要

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor transcription factor that regulates cellular differentiation, adipogenesis, and insulin resistance by recruiting transcriptional coregulator proteins (corepressor and coactivator proteins) to target gene promoters in a ligand-dependent manner. Structure-function approaches have defined how the transcriptionally active structural conformation and coactivator-selective functions of PPARγ are influenced by agonist ligands. However, little is known about the transcriptionally repressive conformation and corepressor-selective functions of PPARγ. Our long-term goal is to close this knowledge gap by defining how different pharmacological PPARγ ligands influence the structure and function of PPARγ between transcriptionally active and repressive states. In preliminary studies, we solved crystal structures of the PPARγ ligand-binding domain (LBD) in a transcriptionally repressive state using a unique corepressor-selective ligand, revealing a unique structural conformation that we have started to validate using solution NMR methods. In this project, we will use mechanistic studies to define how small molecule ligands impact PPARγ activation and repression on the molecular, structural, and cellular levels. Successful outcomes from our studies will define the activity-dependent conformational ensemble of the PPARγ LBD, develop ligands with enhanced corepressor-selective activity, and determine the molecular mechanisms by which corepressor-selective repressive ligands modulate PPARγ cellular functions.

过氧化物酶体增殖体激活受体γ (PPARγ)是一种核受体转录因子

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structural mechanism underlying ligand binding and activation of PPARγ.

DOI：
10.1016/j.str.2021.02.006
发表时间：
2021-09-02
期刊：
Structure (London, England : 1993)
影响因子：
0
作者：
Shang J;Kojetin DJ
通讯作者：
Kojetin DJ

Chemical systems biology reveals mechanisms of glucocorticoid receptor signaling.

DOI：
10.1038/s41589-020-00719-w
发表时间：
2021-03
期刊：
Nature chemical biology
影响因子：
14.8
作者：
Bruno NE;Nwachukwu JC;Srinivasan S;Nettles CC;Izard T;Jin Z;Nowak J;Cameron MD;Boregowda SV;Phinney DG;Elemento O;Liu X;Ortlund EA;Houtman R;Stavreva DA;Hager GL;Kamenecka TM;Kojetin DJ;Nettles KW
通讯作者：
Nettles KW

A molecular switch regulating transcriptional repression and activation of PPARγ