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.

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 Gs which offers insights into the molecular details of ago-allosterism.

Details

Title
Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor
Author
Cong Zhaotong 1 ; Li-Nan, Chen 2 ; Ma Honglei 3 ; Zhou Qingtong 4 ; Zou Xinyu 5 ; Ye Chenyu 1 ; Dai Antao 6 ; Liu, Qing 6   VIAFID ORCID Logo  ; Huang, Wei 7 ; Sun Xianqiang 7 ; Wang, Xi 8 ; Xu Peiyu 3   VIAFID ORCID Logo  ; Zhao, Lihua 3 ; Tian, Xia 5 ; Zhong Wenge 9 ; Yang, Dehua 10   VIAFID ORCID Logo  ; Eric Xu H 8   VIAFID ORCID Logo  ; Zhang, Yan 11   VIAFID ORCID Logo  ; Ming-Wei, Wang 12   VIAFID ORCID Logo 

1  Fudan University, School of Pharmacy, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443); Shanghai Institute of Materia Medica, Chinese Academy of Sciences, The CAS Key Laboratory of Receptor Research, Shanghai, China (GRID:grid.419093.6) (ISNI:0000 0004 0619 8396) 
2  Zhejiang University School of Medicine, Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Hangzhou, China (GRID:grid.13402.34) (ISNI:0000 0004 1759 700X) 
3  Shanghai Institute of Materia Medica, Chinese Academy of Sciences, The CAS Key Laboratory of Receptor Research, Shanghai, China (GRID:grid.419093.6) (ISNI:0000 0004 0619 8396) 
4  Fudan University, School of Basic Medical Sciences, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443) 
5  Huazhong University of Science and Technology, School of Artificial Intelligence and Automation, Wuhan, China (GRID:grid.33199.31) (ISNI:0000 0004 0368 7223) 
6  Chinese Academy of Sciences, The National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai, China (GRID:grid.9227.e) (ISNI:0000000119573309) 
7  Qilu Regor Therapeutics, Inc., Shanghai, China (GRID:grid.9227.e) 
8  Shanghai Institute of Materia Medica, Chinese Academy of Sciences, The CAS Key Laboratory of Receptor Research, Shanghai, China (GRID:grid.419093.6) (ISNI:0000 0004 0619 8396); University of Chinese Academy of Sciences, Beijing, China (GRID:grid.410726.6) (ISNI:0000 0004 1797 8419) 
9  Qilu Regor Therapeutics, Inc., Shanghai, China (GRID:grid.33199.31) 
10  Shanghai Institute of Materia Medica, Chinese Academy of Sciences, The CAS Key Laboratory of Receptor Research, Shanghai, China (GRID:grid.419093.6) (ISNI:0000 0004 0619 8396); Chinese Academy of Sciences, The National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai, China (GRID:grid.9227.e) (ISNI:0000000119573309); University of Chinese Academy of Sciences, Beijing, China (GRID:grid.410726.6) (ISNI:0000 0004 1797 8419) 
11  Zhejiang University School of Medicine, Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Hangzhou, China (GRID:grid.13402.34) (ISNI:0000 0004 1759 700X); Zhejiang University School of Medicine, MOE Frontier Science Center for Brain Research and Brain–Machine Integration, Hangzhou, China (GRID:grid.13402.34) (ISNI:0000 0004 1759 700X); Key Laboratory of Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou, China (GRID:grid.13402.34); Zhejiang University Medical Center, Zhejiang Laboratory for Systems and Precision Medicine, Hangzhou, China (GRID:grid.13402.34) (ISNI:0000 0004 1759 700X); ShanghaiTech University, School of Life Science and Technology, Shanghai, China (GRID:grid.440637.2) (ISNI:0000 0004 4657 8879) 
12  Fudan University, School of Pharmacy, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443); Shanghai Institute of Materia Medica, Chinese Academy of Sciences, The CAS Key Laboratory of Receptor Research, Shanghai, China (GRID:grid.419093.6) (ISNI:0000 0004 0619 8396); Fudan University, School of Basic Medical Sciences, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443); Chinese Academy of Sciences, The National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai, China (GRID:grid.9227.e) (ISNI:0000000119573309); University of Chinese Academy of Sciences, Beijing, China (GRID:grid.410726.6) (ISNI:0000 0004 1797 8419); ShanghaiTech University, School of Life Science and Technology, Shanghai, China (GRID:grid.440637.2) (ISNI:0000 0004 4657 8879) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-021-24058-z
ProQuest document ID
2542529924
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.