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，控制代谢功能和进食行为的关键焦点是黑皮质素受体 MC3R 和 MC4R。这些受体对两种配体（α-黑素细胞刺激激素和刺豚鼠相关蛋白（AgRP））做出反应，它们以相反的方式分别促进负能量平衡和正能量平衡。该项目的目标是了解 MCR 调节的分子基础。上一个资助期的工作揭示了 AgRP 加工的新机制特征，解析了皮肤中发现的同源刺鼠信号蛋白 (ASIP) 的 NMR 结构，并鉴定了免疫系统释放的 2-防御素作为一类新的 MCR 配体。这项研究的下一阶段将通过以下四个项目建立在这些进展的基础上。 1) AgRP N 端结构域极大地抑制了其对 MCR 的亲和力。 NMR、药理学和体内协作研究将用于测试以下假设：部分保守的酸性结构域对接至 C 末端环，从而阻断受体对接。 2) 2-防御素与 AgRP 或 ASIP 不同源，但比较它们各自的结构特征可以识别出可能针对 MCR 的特定环。结构-功能研究将揭示 MCR 的 2-防御素拮抗作用的结构基础。 3) 虽然已发表的工作将 2-防御素 3 确定为 MC1R 和 MC4R 的配体，但初步结果表明其他防御素也能结合。将对 2-防御素家族进行筛选，以确定其他 MCR 相互作用，从而指出潜在的新 2-防御素功能。 4) 2-防御素在体外很难折叠，因此混淆了重要的功能研究。人类 ASIP 也遇到了类似的困难，PI 实验室使用蛋白质工程克服了这些困难。类似的策略将用于 2-防御素家族的成员，以促进对防御素折叠的理解并生产用于药理学和结构研究的有用蛋白质。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。这种情况是由能量摄入和消耗之间的不平衡引起的，会导致糖尿病、高血压、高胆固醇、冠状动脉疾病、胆囊疾病、某些癌症和骨关节炎。在大脑中，黑皮质素系统在控制摄食行为和代谢功能方面发挥着核心作用。黑皮质素受体被认为是主要的治疗靶点。该研究项目利用蛋白质结构测定、蛋白质工程、药理学和筛选来揭示负责黑皮质素系统调节的分子细节。