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

• 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
• 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

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.

过氧化物酶体增殖物激活受体γ (PPARγ) 是一种核受体转录因子， 通过招募转录共调节因子来调节细胞分化、脂肪生成和胰岛素抵抗 蛋白质（辅阻遏蛋白和共激活蛋白）以配体依赖性方式靶向基因启动子。 结构-功能方法已经定义了转录活性结构构象和 PPARγ 的共激活剂选择性功能受激动剂配体的影响。然而，人们对此知之甚少 PPARγ 的转录抑制构象和辅阻遏物选择性功能。我们的长期目标是 通过定义不同药理学 PPARγ 配体如何影响结构来缩小这一知识差距 以及 PPARγ 在转录活性和抑制状态之间的功能。在初步研究中，我们解决了 使用转录抑制状态的 PPARγ 配体结合域 (LBD) 的晶体结构 独特的辅阻遏物选择性配体，揭示了我们已开始验证的独特结构构象 使用溶液核磁共振方法。在这个项目中，我们将利用机理研究来定义小分子如何 配体在分子、结构和细胞水平上影响 PPARγ 的激活和抑制。成功的 我们的研究结果将定义 PPARγ LBD 的活性依赖性构象整体， 开发具有增强的辅阻遏物选择性活性的配体，并通过以下方式确定分子机制 其中辅阻遏物选择性抑制配体调节 PPARγ 细胞功能。

项目成果

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)
• 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

• DOI: 10.1038/s41467-020-14750-x
• 发表时间: 2020-02-19
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Shang, Jinsai;Mosure, Sarah A.;Kojetin, Douglas J.
• 通讯作者: Kojetin, Douglas J.