Linking partial and non-agonist induced dynamics to PPAR gamma functions

描述(申请人提供)：目前处方的胰岛素增敏药物(完整的激动剂罗格列酮和吡格列酮)可与过氧化物酶体增殖物激活的受体PPAR(转录因子)结合，并改善正常血糖水平的维持，这有助于预防糖尿病的长期并发症，包括心脏病和中风，对于2500万美国糖尿病患者中的许多人来说。与二甲双胍和格列本脲等其他药物相比，PPAR结合药物的抗糖尿病效果更持久(更长时间地防止糖尿病进展)，也更有效，使PPA相互作用药物成为治疗糖尿病的宝贵药物。然而，这些药物的使用受到限制，因为它们会导致女性骨折增加、体重增加、心力衰竭和水肿。需要有效的PPAR靶向抗糖尿病患者，减少不良反应。PPAR是一种转录因子，它与许多其他蛋白质相互作用来发挥其作用，它与其表面的这些其他蛋白质相互作用。其中许多相互作用依赖于大而疏水的PPAR配体结合口袋中存在的特定配体。在某种程度上，配体的结合改变了PPAR相互作用表面的结构和/或动力学，从而有利于或不利于与这些伙伴(即共调节因子和异二聚化伙伴，维甲酸X受体，RXR)的相互作用。这种独特的配体诱导(或非配体诱导)的PPAR/Partner复合体增加或减少了许多基因的表达，从而导致体内配体特异性效应。PPAR与许多不同类型的配体结合，无论是单独结合还是与RXR交配，共同调节蛋白和DNA的晶体结构都非常相似，不能解释不同类型PPAR配体的功能差异。我们假设，在这些晶体结构中添加运动信息将有助于将PPAR区域和运动与不同类别的PPAR配体的体内效应关联起来。然后，这种相关性图可以用来推动更有效的PPAR药物开发。我们有证据表明，不同的配体类别(完全、部分和非激动剂)确实可以通过它们诱导的动力学来区分。我们发现，一个与PPAR结合的非激动剂和两个部分激动剂都至少以两种不同的方向与PPAR结合，而有效的激动剂不会。此外，我们的PPAR运动数据提示了PPAR部分激活性的新机制。将PPAR的结构和运动与功能效应联系起来，将有助于改进新型PPAR药物的设计，使其更好地分离有害效应(如心力衰竭)和期望效应(如抗糖尿病疗效、抗炎)。这将改善糖尿病的治疗，并为PPAR针对动脉粥样硬化和自身免疫性疾病的靶向治疗开辟了可能性。 公共卫生相关性：目前的胰岛素增敏药物结合PPAR改变其初级构象和内部运动，这有助于治疗糖尿病，但也会导致体重增加和心力衰竭。我们的建议将确定PPAR的构象和内部运动在与配体相互作用时如何变化，以及这些变化如何促进PPAR的功能。这将增加必要的信息，使有效的PPAR调节剂的开发具有比目前处方药更少的副作用。

DESCRIPTION (provided by applicant): The currently prescribed insulin sensitizing drugs, (the full agonists rosiglitazone and pioglitazone), bind to peroxisome proliferators-activated receptor PPAR, a transcription factor) and improve maintenance of normal blood sugar levels, which helps prevent the long-term complications of diabetes, including heart disease and stroke for many of the 25 million diabetic Americans. The anti-diabetic effects of PPAR binding drugs are more durable (prevent diabetes progression for a longer time) and more effective than other drugs such as metformin and glyburide making PPA interacting drugs a valuable treatment for diabetes. However use of these drugs is limited because they cause increased bone fracture in women, weight gain, heart failure and edema. Effective PPAR targeted anti-diabetics with less unwanted effects are needed. PPAR is a transcription factor that interacts with many other proteins to carry out its effects, it interacts with these other proteins on its surface. Many of these interactions depend on a particular ligand being present in the large and hydrophobic PPAR ligand binding pocket. Somehow, binding of ligand changes the structure and/or dynamics of PPAR's interacting surfaces to favor or disfavor interaction with these partners (i.e. co regulators and heterodimerization partner, retinoid X receptor, RXR). This unique ligand induced (or ligand free) PPAR/partner complex increases or decreases the expression of many genes which leads to ligand specific in vivo effects. PPAR crystal structures bound to many different kinds of ligands, both alone and mated with RXR, co regulator proteins and DNA are very similar and do not explain the functional differences observed for different classes of PPAR ligands. We hypothesize that adding movement information to these crystal structures will help correlate PPAR regions and movements with in vivo effects of the distinct classes of PPAR ligands. This correlation map could then be used to drive more effective PPAR drug development. We have evidence that different ligand classes (full, partial and non agonists) can indeed be differentiated by the dynamics they induce. We have found that a PPAR binding non-agonist and two partial agonists all bind PPAR in at least two distinct orientations, while the ful agonist does not. Furthermore our PPAR movement data suggest a novel mechanism for partial agonism in PPAR. Connection of PPAR structure and movement to functional effects will help improve design of novel PPAR drugs with better separation of unwanted effects (e.g. heart failure) from wanted effects (i.e. anti-diabetic efficacy, anti-inflammation). This will improve diabetes treatment and open up possibilities for PPAR targeted therapies for atherosclerosis and autoimmune disorders. PUBLIC HEALTH RELEVANCE: Current insulin sensitizing drugs bind PPAR changing its primary conformation and its internal movements, which helps treat diabetes but also causes weight gain and heart failure. Our proposal will determine how PPAR conformations and internal movements change as it interacts with ligands and how these changes contribute to PPAR functions. This will add essential information that will allow development of effective PPAR modulators with less side effects than currently prescribed drugs.