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

Zhaotong Cong, Li-Nan Chen, Honglei Ma, Qingtong Zhou, Xinyu Zou, Chenyu Ye, Antao Dai, Qing Liu, Wei Huang, Xianqiang Sun, Xi Wang, Peiyu Xu, Lihua Zhao, Tian Xia, Wenge Zhong, Dehua Yang (), H. Eric Xu (), Yan Zhang () and Ming-Wei Wang ()
Additional contact information
Zhaotong Cong: Fudan University
Li-Nan Chen: Zhejiang University School of Medicine
Honglei Ma: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Qingtong Zhou: Fudan University
Xinyu Zou: Huazhong University of Science and Technology
Chenyu Ye: Fudan University
Antao Dai: Chinese Academy of Sciences
Qing Liu: Chinese Academy of Sciences
Wei Huang: Qilu Regor Therapeutics, Inc.
Xianqiang Sun: Qilu Regor Therapeutics, Inc.
Xi Wang: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Peiyu Xu: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Lihua Zhao: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Tian Xia: Huazhong University of Science and Technology
Wenge Zhong: Qilu Regor Therapeutics, Inc.
Dehua Yang: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
H. Eric Xu: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Yan Zhang: Zhejiang University School of Medicine
Ming-Wei Wang: Fudan University

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract 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 insights into the structural basis of ago-allosterism at GLP-1R and may aid the design of better therapeutics.

Date: 2021
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DOI: 10.1038/s41467-021-24058-z

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