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

大约六分之一的处方药通过与转录因子家族结合而产生治疗效果 称为核受体。此类核受体药物通常为许多患者提供最佳治疗选择。 疾病；然而，它们也会造成严重的不良影响。例如，被称为激动剂的 噻唑烷二酮(TZDS)激活核受体过氧化体增殖物激活受体γ(PPARγ) 而且可以说是治疗II型糖尿病的最好方法；然而，它们会导致体重增加和骨骼虚弱。 一些PPARγ部分激动剂在小鼠身上产生的不良反应较少，但具有相同的有益效果 与TZDS相比。虽然这类新的激动剂很有希望，但它们还没有进入临床。缺乏 对它们如何产生与TZD不同的影响的了解阻碍了它们发展成为治疗药物 II型糖尿病和其他疾病。 我们认为这种部分激动剂是“有偏向的激动剂”。像TZD一样，有偏向的激动剂会结合到 和激活PPARγ；然而，它们通过激活受体而产生不同的效果，与 TZDS。偏向激动剂如何以不同的方式激活受体尚不清楚。 我们知道，激动剂通过招募其他蛋白质，称为共激活蛋白，来产生作用于PPARγ。 核受体偏向激动化的最好支持机制是它们引起我们所说的 “共激活剂偏向”。共激活剂偏向是指激动剂使PPARγ相互作用偏向于某些特定的能力 与TZDS相关的助活剂或远离其他物质。已有文献表明，一些激动剂可诱导共激活剂 偏见；然而，这种偏见从来没有得到很好的量化，而且偏见背后的机制尚不清楚。这 缺乏机械性的理解限制了对进一步发展的热情和能力 偏向PPARγ激动剂。 这项建议将量化和比较一组激动剂的辅助激动剂偏向，并测量急性 这些激动剂对细胞的影响。这将有助于确定共激活子偏向如何影响PPARγ信号 小路。将偏倚与已发表的这些激动剂的生理效应进行比较，可能会将偏倚与 生理效应，包括II型糖尿病药物的预期和不良影响。 该提案还将测试共激活子偏向的结构机制。我们的初步数据显示， 存在两种截然不同的结构类别的共激活剂，这表明了一种明确的机制，即 激动剂倾向于一类结合。完成这项提案的目标将以原子细节定义 PPARγ中偏向激活性的机制。这样的知识对于进一步开发能够 产生较少的不良影响，但保持TZDS的强大和独特的有益影响。因为 PPARγ在结构上与其他核受体相似，在这一提议中获得的知识将影响 对其他核受体有偏见的药物开发。

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.