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（由申请人提供）：人类额外的钙感应受体（CASR）是G蛋白夫妇，它保持Ca2+ tasr的作用在与Ca2+ Balance CH无关的生物过程中也无关紧要。 CA2+的体内疾病包括增强寿命的疾病，CASR的表达改变也是其他疾病，包括CASR的Cancludinger Alzheimer疾病。 GENTS的设计作为二硫键均匀二聚体。旨在理解CASSR在保持结合和特异性的同时，我们提出了与不同和同级群体结合的CASR结构的晶体结构。 G和活跃状态我们计划根据结构来衡量设计的功能效应，以探测配体结合位点和同型拟议研究的第三部分是通过求解CASR的信号转导机制，通过求解全长的结构受体和ITH的下游信号分子。