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

Author:

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,Xu H. EricORCID,Zhang Yan,Wang Ming-Wei

Abstract

AbstractThe 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 Gs. 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 the structural basis of ago-allosterism at GLP-1R and new knowledge to design better therapeutics.

Publisher

Cold Spring Harbor Laboratory

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