胰高血糖素样肽1受体（GLP-1R）可通过结合配基胰高血糖素样肽1进行激活并向下游进行信号转导，从而引发一系列的生理反应，例如胰岛素合成的提高、胰高血糖素水平下降等等。GLP-1R具有较大的细胞外结构域，该结构域在结合配基GLP-1后将其递送于跨膜区并引发整个分子变构，从而启动信号转导通路。GLP-1R介导的信号转导通路在生理血糖控制中具有重要作用，其进行信号转导的结构基础不仅可以阐明B类GPCR的功能机制，而且可为II型糖尿病的药物研发与优化提供指导。本研究拟结合新型膜蛋白结晶技术与抗体工程、高通量活性测定平台来阐明GLP-1R结合天然配基与激动剂/拮抗剂的结构基础，并根据不同状态下的三维结构重建B类GPCR激活进行信号转导的动态过程，同时进一步探索GLP-1R与其下游G蛋白形成复合物的分子机制。

The glucagon like peptide-1 receptor (GLP-1R) is activated upon binding to its ligand glucagon like peptide-1 and in turn conducts signal transduction towards its downstream molecular components to initiate a series of physiological events such as enhancement of insulin production and lowering glucagon level, etc. GLP-1R has a large ectodomain on its N-terimal which can bind GLP-1 and then deliver it into transmembrane domain to induce global conformational change, thereby opening whole signaling pathway. Signal transduction pathway mediated by GLP-1R plays a critical role in control of blood glucose level since the structural basis for GLP-1 signaling can not only elucidate functional mechanism of class-B GPCR, but also provide guide on medicine development and optimization for type II diabetes.The present application is proposed to combine novel technologies in membrane protein crystallography with antibody engineering and high-throughput functional assay platform to investigate the structural basis for binding of GLP-1R to its natural ligands and/or its agonists/antagonists and rebuild a dynamic process for class-B GPCR activation by integrate structures of GLP-1R in different signaling states.