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

约1/6的处方药通过与转录因子家族结合产生治疗效果 称为核受体。这种核受体药物通常为许多人提供最佳治疗选择。 疾病;然而，它们也造成严重的不利影响。例如，已知的激动剂 噻唑烷二酮类（TZDs）激活核受体过氧化物酶体增殖物激活受体γ（PPARγ） 并且可以说是II型糖尿病的最佳治疗方法;然而，它们会导致体重增加和骨质疏松。 一些PPARγ部分激动剂在小鼠中产生较少的副作用，但具有相同的有益作用 与TZD相比。虽然这类新的激动剂很有前途，但它们尚未进入临床。缺乏 了解它们如何产生与TZD不同的作用阻碍了它们开发成治疗药物 II型糖尿病和其他疾病。 我们认为这种部分激动剂是“偏向激动剂”。像TZD一样，偏向性激动剂会结合到 并激活PPARγ;然而，它们会通过激活不同的受体产生不同的效果， TZD。偏性激动剂如何以不同方式激活受体尚不清楚。 我们知道，激动剂通过募集其他蛋白质（称为共激活因子）来产生效应。 核受体中偏向激动作用的最佳支持机制是它们诱导我们所称的 “辅激活因子偏倚”。辅激活因子偏好性是指激动剂使PPARγ相互作用偏向某些特定的受体的能力。 共活化剂或远离相对于TZD的其它共活化剂。有充分的证据表明，一些激动剂诱导辅激活因子 然而，这种偏见从来没有得到很好的量化，偏见背后的机制是未知的。这 缺乏对机械的理解限制了进一步发展的热情和能力。 偏向性的PPARγ激动剂。 该提案将量化和比较一组激动剂的共激活剂偏倚，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因子偏好如何影响PPARγ信号转导 途径。偏倚与这些激动剂已发表的生理效应的比较可能与偏倚相关， 生理作用，包括II型糖尿病药物的期望和不期望的作用。 该提案还将测试共激活剂偏倚的结构机制。初步数据显示， 有两种不同的结构类别的共激活剂，并提出了一个明确的机制， 激动剂有利于一类的结合。完成这项建议的目标将详细界定， 偏性激动的机制。这些知识对于进一步开发药物至关重要， 产生较少的副作用，但保持TZD的强大和独特的有益作用。因为 PPARγ在结构上与其他核受体相似，本提案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.