National Natural Science Foundation of China (NSFC)
81872915
中国
National Natural Science Foundation of China (NSFC)
82073904
中国
National Natural Science Foundation of China (NSFC)
82273961
中国
National Natural Science Foundation of China (NSFC)
32200576
中国
National Natural Science Foundation of China (NSFC)
82273985
中国
National Natural Science Foundation of China (NSFC)
82121005
中国
National Natural Science Foundation of China (NSFC)
81973373
中国
National Natural Science Foundation of China (NSFC)
21704064
中国
引用
ジャーナル: Proc Natl Acad Sci U S A / 年: 2023 タイトル: Structural analysis of the dual agonism at GLP-1R and GCGR. 著者: Yang Li / Qingtong Zhou / Antao Dai / Fenghui Zhao / Rulue Chang / Tianlei Ying / Beili Wu / Dehua Yang / Ming-Wei Wang / Zhaotong Cong / 要旨: Glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR), two members of class B1 G protein-coupled receptors, play important roles in glucose homeostasis and energy metabolism. They ...Glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR), two members of class B1 G protein-coupled receptors, play important roles in glucose homeostasis and energy metabolism. They share a high degree of sequence homology but have different functionalities. Unimolecular dual agonists of both receptors developed recently displayed better clinical efficacies than that of monotherapy. To study the underlying molecular mechanisms, we determined high-resolution cryo-electron microscopy structures of GLP-1R or GCGR in complex with heterotrimeric G protein and three GLP-1R/GCGR dual agonists including peptide 15, MEDI0382 (cotadutide) and SAR425899 with variable activating profiles at GLP-1R versus GCGR. Compared with related structures reported previously and supported by our published pharmacological data, key residues responsible for ligand recognition and dual agonism were identified. Analyses of peptide conformational features revealed a difference in side chain orientations within the first three residues, indicating that distinct engagements in the deep binding pocket are required to achieve receptor selectivity. The middle region recognizes extracellular loop 1 (ECL1), ECL2, and the top of transmembrane helix 1 (TM1) resulting in specific conformational changes of both ligand and receptor, especially the dual agonists reshaped ECL1 conformation of GLP-1R relative to that of GCGR, suggesting an important role of ECL1 interaction in executing dual agonism. Structural investigation of lipid modification showed a better interaction between lipid moiety of MEDI0382 and TM1-TM2 cleft, in line with its increased potency at GCGR than SAR425899. Together, the results provide insightful information for the design and development of improved therapeutics targeting these two receptors simultaneously.