Molecular control of melanocortin receptor signaling

黑皮质素受体信号传导的分子控制

• 批准号: 8000165
• 负责人: GLENN L MILLHAUSER
• 金额: $ 9.78万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8000165
• 关键词: ART protein; Affinity; Binding; Biochemical; Biological Assay; Blood; Body Temperature; Brain; C-terminal; Canis familiaris; Charge; Cholesterol; 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MC 3R和MC 4 R。这些受体响应于两种配体，α-黑素细胞刺激激素和Agouti相关蛋白（AgRP），它们以相反的方式起作用，分别促进负能量和正能量平衡。该计划的目标是了解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，解决了皮肤中发现的同源agraphs信号蛋白（ASIP）的NMR结构，并确定了免疫系统释放的2-防御素作为一类新的MCR配体。本研究的下一阶段将在这些进展的基础上开展以下四个项目。1)AgRP N-末端结构域极大地抑制其对MCR的亲和力。将使用NMR、药理学和体内协作研究来检验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的假设。2)2-防御素与AgRP或ASIP不同源，但它们各自的结构特征的比较确定了可能靶向MCR的特定环。结构-功能研究将揭示MCRs 2-防御素拮抗作用的结构基础. 3)虽然已发表的工作确定2-防御素3作为MC 1 R和MC 4 R的配体，但初步结果表明，其他防御素也结合。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-防御素在体外折叠具有挑战性，因此混淆了重要的功能研究。人类ASIP出现了类似的困难，PI的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，并产生有用的蛋白质用于药理学和结构研究。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消耗之间的不平衡，并导致糖尿病、高血压、高血胆固醇、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进食行为和代谢功能中起着核心作用。黑皮质素受体被确定为主要的治疗靶点。该研究计划使用蛋白质结构测定，蛋白质工程，药理学和筛选来揭示负责调节黑皮质素系统的分子细节。