Molecular determinants of melanocortin 4 receptor for selective agonist binding

描述(申请人提供)：儿童肥胖是现代美国社会的主要健康威胁之一。关于儿童肥胖的一个主要问题是，肥胖儿童患糖尿病、高血压、中风和冠状动脉疾病的风险增加。肥胖是一种特别具有挑战性的医学状况，因为它的病因是多因素的，而且现有的治疗局限性。黑素皮质素-4受体(MC4R)在调节食物摄入量和体重方面起着关键作用。我们的长期目标是阐明hMC4R负责配体结合和信号传递的分子基础，这是开发用于治疗肥胖的选择性MC4R非肽激动剂的必要前提。我们推测hMC4R跨膜区的独特氨基酸残基参与了MC4R激动剂的选择性结合。为了验证这一假设，我们将利用1)选择性激动剂的新型光亲和标记来研究配体与MC4R之间的直接相互作用，以及2)利用相互配基和受体残基交换来鉴定选择性激动剂与MC4R之间的直接相互作用。我们提出的研究将为配体结合、受体信号转导提供最精细的分子细节，并将为设计可用于治疗人类肥胖的选择性MC4R激动剂提供有价值的信息。肥胖是现代美国社会面临的主要健康威胁之一。本R03的应用是为了探索黑素皮质素4受体参与激动剂活性的分子基础，可用于开发肥胖的新治疗方法。

DESCRIPTION (provided by applicant): Childhood obesity is one of the major health threats for modern American society. A major concern regarding childhood obesity is that obese children face an increased risk of diabetes mellitus, hypertension, stroke and coronary artery diseases. Obesity is a particularly challenging medical condition to treat because of its multi-factorial etiology and existing therapeutic limitations. The melanocortin-4 receptor (MC4R) has been identified to play a key role in the regulation of food intake and body weight. Our long term goal is to elucidate the molecular basis of hMC4R responsible for ligand binding and signaling as a necessary prerequisite to the development of selective MC4R nonpeptide agonist for therapeutic treatment of obesity. We hypothesize that unique amino acid residues in the transmembrane domains of hMC4R are involved in the selective MC4R agonist binding. To test this hypothesis, we will utilize 1) novel photoaffinity labeling of selective agonist to examine the direct interaction between the ligand and MC4R, and 2) identify the direct interactions between selective agonist and MC4R using reciprocal ligand and receptor residue exchange. Our proposed studies will provide the finest level of molecular detail for ligand binding, receptor signaling and will provide valuable information for designing selective MC4R agonists that may be used in the treatment of human obesity. Obesity is one of the major health threats facing modern American society. This R03 application is to explore the molecular basis of melanocorin 4 receptor responsible for agonist activity which can be used to develop new therapuetic approach for obesity.