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

By Zhaotong Cong, Li-Nan Chen, Honglei Ma, Qingtong Zhou, Xinyu Zou, Chenyu Ye, Antao Dai, Qing Liu, Wei Huang, Xiangqiang Sun, Xi Wang, Peiyu Xu, Lihua Zhao, Tian Xia, Wenge Zhong, Dehua Yang, H. Eric Xu, Yan Zhang, Ming-Wei Wang

Posted 29 May 2021
bioRxiv DOI: 10.1101/2021.05.29.446269

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 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.

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