G蛋白偶联受体（GPCR）是重要的药物靶标。针对GPCR的药物占据了市场药物的30%。现在尚有约100种GPCR孤儿受体（oGPCR），是潜在的新药物靶点。oGPCR脱孤和配体发现是GPCR药理学研究热点。申请人前期工作系统的阐释了GPCR家族C成员mGluR和GABAB受体不同结构域的精细构象变化机制，并建立了从受体到G蛋白和β-arrestin到下游蛋白激酶的多层面功能检测平台。本项目将针对GPCR家族C中的CaSR、GPRC6A和oGPCR（GPR158和GPR179），开发基于构象变化的配体鉴定新方法，结合现有功能检测平台，多方法联用，发现可激活受体的特异性配体包括激动剂和变构剂；进一步，深入研究配体的激活机制和下游信号通路。本项目将为以oGPCR为新药物靶标的鉴定提供新技术与新方法，为靶向C组GPCR的药物开发提供理论基础和干预新方案。

G protein coupled receptors (GPCRs) are important drug targets. More than 30% of the drugs in the market with best drug-able ability. Now there are still about 100 orphan GPCRs (oGPCR), which are potential new drug targets. The drug discovery for oGPCR depends on pharmacological and genetic methods, which are limited. Our group focused on the structure and function analysis on group C GPCRs such as mGluRs and GABAB receptors. We have illustrated the allosteric interaction between different sub-domains of GPCR dimers during activation and set up one set of cell based function assays for GPCR activation such as G protein/β-arrestin coupling and downstream kinase activation. This project will study several orphan GPCR of the group C GPCRS, including CaSR、GPRC6A and oGPCR. We will first develop novel functional assays to identify the ligands of group C oGPCR. Furthermore, we will identify the ligand binding site and the interface for the dynamic conformational change of these GPCRs. Finally, we will characterize the downstream signal transduction pathway. This project will provide new method to deorphanize group C oGPCRs.