Thyroid Hormone Receptor

描述(申请人提供)：核受体(NRs)是最重要的调节分子之一，也是药物开发的主要靶点。NRs受各种小分子配体的调节，既可以作为激动剂，也可以作为拮抗剂。这类NR配体约占所有药物的20%，用于治疗糖尿病、动脉粥样硬化、自身免疫性疾病和癌症等多种疾病。甲状腺激素受体(TH)调节动脉粥样硬化、肥胖和糖尿病的重要过程。多年来，生物学中一些最具启发性的发现来自于对大分子原子结构的确定。我们的团队一直在使用X射线结晶学和越来越多的其他方法来确定TR配体结合结构域(LBD)的原子结构。这些结构信息，以及其他人获得的信息，揭示了受体功能的多个方面，并有助于刺激学术界和制药/生物技术行业的NR药物开发。选择性受体激动剂在治疗动脉粥样硬化、肥胖症和糖尿病的动物试验中显示出巨大的前景，现在正在进行人类临床试验。我们还在雄激素受体(AR)拮抗剂的设计方面取得了进展，以解决几个问题，包括由于TH过剩和癌症耐药造成的问题。我们建议通过应用各种互补的结构方法来获得进一步的见解，包括X射线结晶学、氢-氘交换、分子动力学模拟、小角X射线溶液散射和核磁共振(核磁共振)。我们希望了解激素结合口袋和受体表面活性构象的变化，配体对受体构象和功能的影响，配体结合的选择性机制和拮抗剂作用机制。我们将用天然序列或疾病中出现的自然突变或稳定TRs的人工突变来检查LBD。LBD要么与不同结构的激动剂或拮抗剂结合(包括结合tr表面的小分子)，要么与稳定的伙伴去连接，如辅阻遏肽和二聚体/异二聚体伙伴。由于LBD影响其他受体结构域，反之亦然，并且受体的活性受DNA结合的调节，我们也将通过获得与其DNA结合结构域(DBD)或全长受体DNA相连的TRLBD的结构信息来了解这些相互作用。如上所述，这些结构将用突变、异二聚体配对和辅助调节多肽进行分析。总之，这些研究应该为NR在健康和疾病中的作用提供新的见解，并将告诉我们如何设计策略来调节它们的功能。 甲状腺激素可以激发许多可能有助于治疗/预防动脉粥样硬化(包括心脏病发作、中风、肾脏疾病和外周血管疾病)、肥胖和糖尿病的行动，但也会产生不良影响。拟议中的研究将有助于更好地了解甲状腺激素发挥作用的受体，并应有助于设计具有预期但非有害影响的甲状腺激素等药物。这些研究还应该得出一些原则，这些原则可能对开发治疗其他一些疾病的药物有用。

DESCRIPTION (provided by applicant): Nuclear receptors (NRs) are one of the most important classes of regulatory molecules and major targets for pharmaceutical development. NRs are regulated by various small molecule ligands, acting as either agonists or antagonists. Such NR ligands account for about 20% of all pharmaceuticals and are used to treat conditions as diverse as diabetes, atherosclerosis, autoimmune disorders and cancer. Thyroid hormone (TH) receptors (TRs) regulate important processes involved in atherosclerosis, obesity and diabetes. Over the years, some of the most revealing discoveries in biology have come from determinations of atomic structures of large molecules. Our group has been determining atomic structures of TR ligand-binding domains (LBDs), using X- ray crystallography, and increasingly, other methods. This structural information, along with that obtained by others, has revealed multiple aspects of receptor function, and has helped to stimulate NR drug development within academia and the pharmaceutical/biotechnology industry. Selective TR agonists have shown great promise in animal trials for treating atherosclerosis, obesity and diabetes, and are now in human clinical trials. We have also made progress with TR and androgen receptor (AR) antagonist design to attack several problems, including those due to TH excess and drug resistance in cancer. We propose to obtain further insights through application of a variety of complementary structural approaches, including X-ray crystallography, hydrogen-deuterium exchange, molecular dynamics simulations, small angle X-ray solution scattering and nuclear magnetic resonance (NMR). We hope to understand variations in the active conformation in the hormone binding pocket and on the receptor surface, ligand effects on receptor conformation and function, mechanisms of selectivity in ligand binding and mechanisms of antagonist action. We will examine LBDs with native sequences or with natural mutations that occur in disease or artificial mutations that stabilize TRs. LBDs will either be bound to different agonists or antagonists with diverse structures (including small molecules that bind the TR surface) or unliganded with stabilizing partners, such as corepressor peptides and dimer/heterodimer partners. Since the LBD influences other receptor domains, and vice versa, and receptor activity is modulated by DNA binding we will also seek to understand these interactions by obtaining structural information about the TR LBD linked to its DNA-binding domain (DBD) or the full length receptor DNA. These structures will be analyzed with mutations, heterodimer partner and coregulator peptides as described above. Together, these studies should provide new insights into NR function in health and disease and will tell us how to devise strategies to modulate their function. Thyroid hormones elicit many actions that could be useful for treating/preventing atherosclerosis (including heart attack, stroke, kidney disease and peripheral vascular disease), obesity and diabetes, but also have undesirable effects. The proposed studies will help to better understand the receptors through which thyroid hormones work and should facilitate design of thyroid hormone like pharmaceuticals that have desired but not unwanted effects. The studies should also lead to principles that can be useful for developing pharmaceuticals that attack a number of other conditions.