基于受体蛋白结构信息阐释GLP-1R和GCGR受体选择性的分子机制

胰高血糖素样肽-1受体（GLP-1R）和胰高血糖素受体（GCGR）同属于B类GPCR，均为当今公认的重要抗糖尿病药物作用靶点。二者具有47%的同源性，但其生理功能却截然相反，明确两个受体功能选择性的分子机制对于理解其作用模式及以此为靶点的药物开发至关重要。我们在2013年首次解析了GCGR的跨膜区三维结构，近期又解析了全长GCGR以及GLP-1R跨膜区的结构，这为我们研究受体功能选择性指明了方向。基于两个受体与小分子化合物结合的结构信息，我们将系统评价三维结构中关键氨基酸位点的功能，通过构建GLP-1R/GCGR的嵌合受体和突变体，分别阐明两个受体与不同小分子配体及肽类配体选择性结合并启动下游信号转导的分子机制。本课题的开展对于深入理解GLP-1R/GCGR的功能、作用机制以及小分子药物的精准设计与开发具有重要的意义。

Glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) belong to class B GPCRs and play important roles in regulating glucose homeostasis which attracted considerable interest as targets in the treatment of type 2 diabetes. GLP-1R exhibits 47% sequence identity with GCGR while acts opposite biological effects. It is crucial to understand how the homologous GCGR and GLP-1R dstinguish between their homologous ligands glucagon and GLP-1, not only for the study of molecular determinants, but also for drug design and development. We have previously determined the three-dimensional atomic structure of the transmembrane domain (TMD) of human GCGR in 2013, and recently solved the full-length GCGR and GLP-1R-TMD. Based on the crystal structures of the two receptors, we aim at evaluating the function and downstream signal of key residues from structure information and elucidating the molecular mechanism of peptidic and non-peptidic ligand selectivity for both receptors. The outcome of this study will deepen our knowledge on GLP-1R/GCGR function and facilitate its drug discovery.