胰高血糖素家族GPCR的受体间相互作用及其多重药理学分子机制的研究

胰高血糖素家族受体是B类GPCR中重要的糖尿病药物作用靶标，其中GLP-1R、GCGR、GIPR三个受体具有超过40%的同源性，但其糖代谢调节功能却截然不同。近年来，针对三个受体的多重激动剂显示了效果更优的疗效并已成为当前药物开发的热点，然而其多重药理学分子机制仍未阐明。本项目将基于我们在该家族受体的结构解析、功能研究和小分子配体开发中的研究成果，围绕多重激动剂的调控网络和GLP-1R/GCGR/GIPR的受体二聚化，从配体和受体两个层面阐释多重激动剂协同调控受体的作用以及该家族受体二聚化的组成和功能，在此基础上深入研究多重激动剂与受体结合的关键位点及其在偏向调节、变构调节和受体二聚化动态调节中的分子机制。同时，我们将在三个受体高表达的胰岛β细胞中深入研究其多重药理学作用的生理意义。本课题的开展对于深入理解该家族受体的多重药理学分子机制以及精准药物设计与开发具有重要的理论和应用价值。

The glucagon subfamily of class B G protein-coupled receptors (GPCRs) has been proposed to be crucial drug targets for the treatment of type 2 diabetes. Glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) exhibit more than 40% sequence identity with glucagon receptor (GCGR), while acts opposite biological effects. Recently, single-molecule peptides integrating the complementary actions of GLP-1R/GCGR/GIPR have emerged as one of the more promising clinical candidates for reversing diabetes and obesity. However, the mechanism of its polypharmacology is unclear. We have previously determined the three-dimensional atomic structure of the transmembrane domain (TMD) of human GCGR in 2013, and recently solved the structures of full-length GCGR and GLP-1R-TMD. Based on the crystal structures, functional studies and small molecular ligand development of these three receptors, we aim at evaluating the binding and signal profiles of dual and triple agonists, as well as the homo- and heterodimer of GLP-1R/GCGR/GIPR. Furthermore, we will define the key residues and molecular mechanism of their bias signal, allosteric regulation and dimerization. In addition, we will characterise the physiological importance for polypharmacology and dimerization in pancreatic beta cells. The outcome of this study will deepen our knowledge on GLP-1R/GCGR/GIPR function and facilitate its drug discovery.