Structural definition of biased agonism in the nuclear receptor PPAR gamma.

核受体 PPAR γ 偏向激动的结构定义。

• 批准号: 10667641
• 负责人: Travis Shane Hughes
• 金额: $ 36.91万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667641
• 关键词: Acute; Adipocytes; Adverse effects; Affect; Affinity; Agonist; Animals; Autoimmune Diseases; Automobile Driving; Binding; Cells; Characteristics; Clinic; Complex; Crystallography; Data; Deuterium; Development; Disease; Drug Prescriptions; Drug Receptors; Drug Targeting; Dyslipidemias; Encyclopedias; Evaluation; Family; Fluorescence Anisotropy; Fluorine; Fracture; Gene Expression Profile; Genes; Genetic Transcription; Genome; Goals; Heart failure; Human; Hydrogen; Investments; Knowledge; Lead; Ligands; Mass Spectrum Analysis; Measures; Mediating; Metabolic syndrome; Molecular; Mus; Mutagenesis; N-terminal; Names; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Magnetic Resonance; Nuclear Receptors; Outcome; PPAR gamma; Pathway Analysis; Peptides; Pharmaceutical Preparations; Physiological; Proteins; Publishing; Reporting; Sales; Series; Signal Pathway; Signal Transduction; Structure; Testing; Therapeutic; Therapeutic Effect; Thiazolidinediones; Weight Gain; Work; antagonist; bone; chronic liver disease; clinically relevant; design; drug development; drug discovery; fracture risk; improved; improved outcome; molecular dynamics; novel; programs; receptor; receptor structure function; recruit; transcription factor; transcriptome sequencing; Acute; Adipocytes; Adverse effects; Affect; Affinity; Agonist; Animals; Autoimmune Diseases; Automobile Driving; Binding; Cells; Characteristics; Clinic; Complex; Crystallography; Data; Deuterium; Development; Disease; Drug Prescriptions; Drug Receptors; Drug Targeting; Dyslipidemias; Encyclopedias; Evaluation; Family; Fluorescence Anisotropy; Fluorine; Fracture; Gene Expression Profile; Genes; Genetic Transcription; Genome; Goals; Heart failure; Human; Hydrogen; Investments; Knowledge; Lead; Ligands; Mass Spectrum Analysis; Measures; Mediating; Metabolic syndrome; Molecular; Mus; Mutagenesis; N-terminal; Names; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Magnetic Resonance; Nuclear Receptors; Outcome; PPAR gamma; Pathway Analysis; Peptides; Pharmaceutical Preparations; Physiological; Proteins; Publishing; Reporting; Sales; Series; Signal Pathway; Signal Transduction; Structure; Testing; Therapeutic; Therapeutic Effect; Thiazolidinediones; Weight Gain; Work; antagonist; bone; chronic liver disease; clinically relevant; design; drug development; drug discovery; fracture risk; improved; improved outcome; molecular dynamics; novel; programs; receptor; receptor structure function; recruit; transcription factor; transcriptome sequencing

About 1 out of 6 prescription drugs produce therapeutic effects by binding to a family of transcription factors called nuclear receptors. Such nuclear receptor drugs often provide the best treatment option for many diseases; however, they also cause serious adverse effects. For example, agonists known as thiazolidinediones (TZDs) activate the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) and are arguably the best treatment for type II diabetes; however, they cause weight gain and weak bones. Some PPARγ partial agonists produce fewer adverse effects but the same beneficial effects in mice compared to TZDs. While this new class of agonists is promising, they have not reached the clinic. A lack of understanding of how they produce different effects from TZDs impedes their development into drugs to treat type II diabetes and other diseases. We propose that such partial agonists are “biased agonists”. Like TZDs, a biased agonist would bind to and activate PPARγ; however, they would produce different effects by activating the receptor differently from TZDs. How biased agonists could activate the receptor differently is not known. We know that agonists produce effects by recruiting other proteins, known as coactivators, to PPARγ. The best-supported mechanism of biased agonism in nuclear receptors is that they induce what we term “coactivator bias”. Coactivator bias refers to the ability of an agonist to bias interaction of PPARγ toward certain coactivators or away from others relative to TZDs. It is well-documented that some agonists induce coactivator bias; however, such bias has never been well-quantified and the mechanism underlying bias is unknown. This lack of mechanistic understanding limits enthusiasm for and the ability to carry out further development of biased PPARγ agonists. This proposal will quantify and compare coactivator bias for a panel of agonists and measure the acute effects of those same agonists on cells. This will help determine how coactivator bias affects PPARγ signaling pathways. Comparison of bias with the published physiologic effects of these agonists may correlate bias with physiologic effects, including the desired and undesired effects of type II diabetes drugs. This proposal will also test structural mechanisms of coactivator bias. Our preliminary data show that there are two distinct structural classes of coactivators and suggest a clear mechanism by which biased agonists favor binding of one class. Completion of the aims of this proposal will define, in atomic detail, mechanisms of biased agonism in PPARγ. Such knowledge is critical to further development of drugs that produce less adverse effects, but maintain the powerful and unique beneficial effects of TZDs. Because PPARγ is structurally similar to other nuclear receptors, the knowledge gained in this proposal will impact biased drug development for other nuclear receptors.

6种处方药中约有1种通过与转录因子系列结合产生治疗作用 称为核接收器。这种核接收器药物通常为许多人提供最好的治疗选择 疾病；但是，它们也会引起严重的不利影响。例如，激动剂被称为 噻唑烷二酮（TZDS）激活核受体过氧化物增生剂激活受体γ（PPARγ） 可以说是II型糖尿病的最佳治疗方法；但是，它们会导致体重增加和骨骼弱。 一些PPARγ部分激动剂产生的不利影响较少，但在小鼠中产生相同的有益作用 与TZD相比。尽管这种新的激动剂是有希望的，但他们尚未到达诊所。缺乏 了解它们如何产生与TZD的不同影响会阻碍其发展为药物治疗 II型糖尿病和其他疾病。 我们建议这样的部分激动剂是“偏见的激动剂”。像TZD一样，有偏的激动剂会与 并激活PPARγ；但是，它们会通过与接收器不同而不同地产生不同的影响 TZD。尚不清楚偏见的激动剂如何以不同的方式激活接收器。 我们知道，激动剂通过募集其他蛋白质（称为共激活剂）为PPARγ产生影响。 核接收器中有偏见激动剂的最佳支撑机制是，它们会影响我们所说的 “共激活因子偏见”。共激活因子偏差是指激动剂偏向PPARγ相互作用的能力 相对于TZD的共激活因子或远离他人。有充分记录的一些激动剂会诱导共激活因子 偏见;但是，这种偏见从未得到充分验证，偏见的机制尚不清楚。 缺乏机械理解限制了热情和进一步发展的能力 偏见的PPARγ激动剂。 该提案将量化和比较一组激动剂的共激活因子偏差，并测量急性 那些激动剂对细胞的影响。这将有助于确定共激活因子如何影响PPARγ信号传导 途径。偏见与这些激动剂的发表生理效应的比较可能与偏见相关 生理作用，包括II型糖尿病药物的所需和不希望的作用。 该建议还将测试共激活因子偏置的结构机制。我们的初步数据表明 共激活因子有两个不同的结构类别，并提出了一种清晰的机制 激动剂赞成一个班级的约束。该提案目标的完成将以原子细节定义 PPARγ中偏置激动剂的机制。这种知识对于进一步开发药物至关重要 产生较小的不利影响，但保持TZD的强大和独特的有益作用。因为 PPARγ在结构上与其他核接收器相似，该提案中获得的知识将影响 其他核接收器的药物开发有偏见。