Molecular control of melanocortin receptor signaling

黑皮质素受体信号传导的分子控制

• 批准号: 7676549
• 负责人: GLENN L MILLHAUSER
• 金额: $ 33.32万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7676549
• 关键词: ART protein; Affinity; Binding; Biochemical; Biological Assay; Blood; Body Temperature; Brain; C-terminal; Canis familiaris; Charge; Cholesterol; Classification; Cleaved cell; Color; Complex; Coronary Arteriosclerosis; Defensins; Degenerative polyarthritis; Diabetes Mellitus; Disulfide Linkage; Docking; Drosophila pros protein; Energy Intake; Exhibits; Expenditure; Family; Feeding behaviors; Funding; G Protein-Coupled Receptor Genes; Gall Bladder Diseases; Goals; Hair; Hormones; Human; Hypertension; Immune system; In Vitro; Individual; Investigation; Lead; Length; Ligands; Malignant Neoplasms; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; Molecular; Muscle Development; Mutagenesis; Mutation; N-terminal; Obesity; Pattern; Pharmacology; Phase; Physiological; Pigmentation physiologic function; Play; Process; Production; Protein Engineering; Proteins; Public Health; Publishing; Reagent; Receptor Signaling; Regulation; Research; Role; Screening procedure; Skin; Societies; Specificity; Structure; System; Testing; Tissues; Work; agouti protein; alpha-Melanocyte stimulating hormone; base; bone; design; energy balance; feeding; in vivo; melanocortin receptor; member; mouse nonagouti protein; mutant; programs; protein structure; public health relevance; receptor; receptor binding; research study; therapeutic target

DESCRIPTION (provided by applicant): In the brain, key focal points for control of metabolic function and feeding behavior are melanocortin receptors MC3R and MC4R. These receptors respond to two ligands, alpha-melanocyte stimulating hormone and Agouti-related protein (AgRP), which act in opposite ways to promote negative and positive energy balance, respectively. The goal of this program is to understand the molecular basis of MCR regulation. Work from the last funding period uncovered new mechanistic features of AgRP processing, solved the NMR structure of the homologous agouti signaling protein (ASIP) found in the skin, and identified 2-defensins, released by the immune system, as a new class of MCR ligands. The next phase of this research will build on these advances with the following four projects. 1) The AgRP N-terminal domain greatly inhibits its affinity for MCRs. NMR, pharmacology and collaborative in vivo studies, will be used to test the hypothesis that a partially conserved acidic domain docks to a C-terminal loop thus occluding receptor docking. 2) 2-Defensins are not homologous to AgRP or ASIP, but comparison of their respective structural features identifies specific loops that may target MCRs. Structure- function studies will uncover the structural basis for 2-defensin antagonism of MCRs. 3) Although published work identifies 2-defensin 3 as a ligand to MC1R and MC4R, preliminary results show that other defensins bind as well. A screen across the family of 2-defensins will be performed to identify additional MCR interactions, thus pointing to potential new 2-defensin functions. 4) 2-Defensins are challenging to fold in vitro, thus confounding important functional investigations. Human ASIP presented similar difficulties that were overcome by the PI's lab using protein engineering. Analogous strategies will be used with members of the 2-defensin family to advance the understanding of the defensin fold and to produce useful protein for pharmacological and structural studies. PUBLIC HEALTH RELEVANCE: Obesity is one of the greatest public health concerns facing Western society. The condition arises from an imbalance between energy intake and expenditure and contributes to diabetes, high blood pressure, high blood cholesterol, coronary artery disease, gallbladder disease, certain cancers and osteoarthritis. In the brain, the melanocortin system plays a central role in controlling feeding behavior and metabolic function. Melanocortin receptors are identified as prime therapeutic targets. This research program uses protein structure determination, protein engineering, pharmacology and screening to uncover the molecular details responsible for regulation of the melanocortin system.

描述（由申请人提供）：在大脑中，用于控制代谢功能和喂养行为的关键焦点是黑色皮质素受体MC3R和MC4R。这些受体对两种配体的反应，α-甲状腺细胞刺激激素和与Agouti相关的蛋白质（AGRP），它们以相反的方式作用，分别促进负能量和正能量平衡。该程序的目的是了解MCR调节的分子基础。从上一个资金期开始的工作发现了AGRP加工的新机械特征，解决了在皮肤中发现的同源Agouti信号蛋白（ASIP）的NMR结构，并鉴定出由免疫系统释放的2-二防御素，作为新的MCR配体。这项研究的下一阶段将以以下四个项目为基于这些进步。 1）AGRP N末端结构域极大地抑制了其对MCR的亲和力。 NMR，药理学和体内研究协作，将用于检验以下假设：部分保守的酸性结构域对接到C末端环，从而阻塞受体对接。 2）2-防御素与AGRP或ASIP不是同源的，但是它们各自的结构特征的比较标识了可能针对MCR的特定环路。结构 - 功能研究将发现MCR的2-防御素拮抗作用的结构基础。 3）尽管已发表的工作将2-防御素3鉴定为MC1R和MC4R的配体，但初步结果表明，其他防御素也结合了。将执行各个二防御素家族的屏幕，以识别其他MCR相互作用，从而指出潜在的新2-防御素功能。 4）2-防御素在体外折叠方面具有挑战性，从而使重要的功能研究混淆。人类ASIP带来了类似的困难，这些困难被PI的实验室使用蛋白质工程所克服。将与2-防御素家族的成员一起使用类似的策略，以提高对防御素折叠的理解，并为药理学和结构研究产生有用的蛋白质。公共卫生相关性：肥胖是西方社会面临的最大公共卫生问题之一。这种情况源于能量摄入和支出之间的不平衡，并导致糖尿病，高血压，高血液胆固醇，冠状动脉疾病，胆囊疾病，某些癌症和骨关节炎。在大脑中，黑色皮质素系统在控制喂养行为和代谢功能方面起着核心作用。黑色皮质素受体被鉴定为主要治疗靶标。该研究计划使用蛋白质结构确定，蛋白质工程，药理学和筛查，以发现负责调节黑素皮质系统系统的分子细节。