Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor

• Published in: Nature communications 2021-06, Vol.12 (1), p.3763-3763, Article 3763
• Main Authors: Cong, Zhaotong, Chen, Li-Nan, Ma, Honglei, Zhou, Qingtong, Zou, Xinyu, Ye, Chenyu, Dai, Antao, Liu, Qing, Huang, Wei, Sun, Xianqiang, Wang, Xi, Xu, Peiyu, Zhao, Lihua, Xia, Tian, Zhong, Wenge, Yang, Dehua, Eric Xu, H., Zhang, Yan, Wang, Ming-Wei
• Format: Article
• Language: English
• Subjects: 101/28; 13/109; 13/95; 631/154/436/2387; 631/45/612/194; 631/535/1258/1259; 631/57/2266; 82/29; 82/80; 82/81; 82/83; Agonists; Allosteric properties; Binding sites; Chemical bonds; Coupling (molecular); Diabetes mellitus (non-insulin dependent); Electron microscopy; Glucagon; Glucagon-like peptide 1; Homeostasis; Humanities and Social Sciences; Metabolic disorders; Modulation; Modulators; multidisciplinary; Peptides; Receptors; Science; Science (multidisciplinary); Side effects; Therapeutic targets
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-24058-z

The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric G s . The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site. This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling. Our findings offer insights into the structural basis of ago-allosterism at GLP-1R and may aid the design of better therapeutics. The glucagon-like peptide-1 (GLP-1) receptor is a key regulator of glucose homeostasis and a drug target for type 2 diabetes but available GLP-1R agonists are suboptimal due to several side-effects. Here authors report the cryo-EM structure of GLP-1R bound to an ago-allosteric modulator in complex with heterotrimeric G s which offers insights into the molecular details of ago-allosterism.