Structural studies of human extracellular calcium-sensing receptor

人细胞外钙敏感受体的结构研究

基本信息

批准号：
9293333
负责人：
QING R FAN
金额：
$ 31.6万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9293333
关键词：
Affect Affinity Agonist Alzheimer&apos s Disease Amino Acids Binding Binding Sites Biological Process Bone Diseases Calcium Calcium-Sensing Receptors Calmodulin Cell Extracts Cell membrane Cell surface Cells Clinical Complex Cryoelectron Microscopy Crystallization Cytoplasmic Receptors Cytoplasmic Tail Detergents Dimerization Disease Disulfides Equilibrium Event Exhibits Extracellular Domain Fetal Development G-Protein-Coupled Receptors G-substrate GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Goals Heterotrimeric GTP-Binding Proteins Homeostasis Homodimerization Homology Modeling Human Inositol Phosphates Insecta Intracellular Signaling Proteins Ions Lead Length Life Ligand Binding Ligands Maintenance Malignant Neoplasms Mammalian Cell Maps Measures Metabolism Methods Minerals Molecular Molecular Conformation Monitor Mutation PTH gene Phenylalanine Physiological Play Proteins Receptor Activation Receptor Gene Regulation Research Rest Role Signal Pathway Signal Transduction Signaling Molecule Site Specificity Stimulus Structural Models Structure System Therapeutic Agents Transmembrane Domain X-Ray Crystallography base cinacalcet design detection of nutrient dimer extracellular information model neuronal excitability novel therapeutics public health relevance receptor receptor function response

项目摘要

DESCRIPTION (provided by applicant): Human extracellular calcium-sensing receptor (CaSR) is a G-protein coupled receptor that maintains Ca2+ homeostasis through the regulation of parathyroid hormone secretion. CaSR also plays important roles in biological processes unrelated to Ca2+ balance such as fetal development. Abnormalities in the CaSR gene are associated with a vareity of Ca2+ homeostatic disorders including potentially life threatening hypercalcaemic conditions. Altered expression of CaSR has also been implicated in other diseases including cancer and Alzheimer's disease. Cinacalcet, an allosteric modulator of CaSR, is used clinically to treat disorders of bone and mineral metabolism. Therefore, elucidating the structure of CaSR may assist the design of valuable therapeutic agents. CaSR functions as a disulfide-tethered homodimer. It activates a diverse array of signaling pathways in a ligand-specific manner. In addition to its principal agonist, extracellular Ca2+, CaSR responds to a variety of agonists, and its activity is regulated by postive and negative allosteric modulators. The first part of this proposal is aimed at understanding the mechanisms by which CaSR recognizes structurally distinct ligands while maintaining binding affinity and specificity. We propose to solve the crystal structures of CaSR ectodomain bound to different agonists and allosteric modulators. The second aim is to identify the conformational changes associated with receptor activation based on the structures of CaSR ectodomain in the resting and active states. We plan to measure the functional effects of mutations that are designed based on these structures to probe the ligand binding sites and homodimer interface. The third part of the proposed research is to elucidate the signal transduction mechanism of CaSR by solving the structures of full-length receptor and its complexes with downstream signaling molecules. A combination of structural and functional analysis of CaSR will advance our understanding of the molecular basis of extracellular Ca2+ sensing and the general activation mechanisms of GPCR dimers.

描述（申请人提供）：人细胞外钙敏感受体（CaSR）是一种 G 蛋白偶联受体，通过调节甲状旁腺激素分泌来维持 Ca2+ 稳态，CaSR 在与 Ca2+ 平衡无关的生物过程（如胎儿）中也发挥着重要作用。 CaSR 基因的异常与多种 Ca2+ 稳态紊乱有关，包括可能危及生命的高钙血症。西那卡塞是一种 CaSR 变构调节剂，与癌症和阿尔茨海默病等其他疾病有关，在临床上用于治疗骨和矿物质代谢紊乱，因此，阐明 CaSR 的结构可能有助于设计有价值的治疗药物。二硫键连接的同二聚体。它以配体特异性方式激活多种信号通路。除了其主要激动剂细胞外 Ca2+ 外，CaSR 还对多种信号通路做出反应。该提案的第一部分旨在了解 CaSR 识别结构不同的配体同时保持结合亲和力和特异性的机制。第二个目的是根据静息和活性状态下的 CaSR 胞外域结构来识别与受体激活相关的构象变化。基于这些结构设计的突变的功能效应，以探测配体结合位点和同二聚体界面。本研究的第三部分是通过解析全长受体及其复合物的结构来阐明CaSR的信号转导机制。 CaSR 的结构和功能分析相结合将促进我们对细胞外 Ca2+ 传感的分子基础和 GPCR 二聚体的一般激活机制的理解。