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; Ming-Wei Wang

doi:10.1038/s41467-021-24058-z

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

Nat Commun. 2021 Jun 18;12(1):3763. doi: 10.1038/s41467-021-24058-z.

Authors

Zhaotong Cong^#^{1

2}, Li-Nan Chen^#³, Honglei Ma^#², Qingtong Zhou^#⁴, Xinyu Zou⁵, Chenyu Ye^{1

2}, Antao Dai⁶, Qing Liu⁶, Wei Huang⁷, Xianqiang Sun⁷, Xi Wang^{2

8}, Peiyu Xu², Lihua Zhao², Tian Xia⁵, Wenge Zhong⁷, Dehua Yang^{9

10

11}, H Eric Xu^{12

13}, Yan Zhang^{14

15

16

17

18}, Ming-Wei Wang^{19

20

21

22

23

24}

Affiliations

¹ School of Pharmacy, Fudan University, Shanghai, China.
² The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
³ Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁴ School of Basic Medical Sciences, Fudan University, Shanghai, China.
⁵ School of Artificial Intelligence and Automation, Huazhong University of Science and Technology, Wuhan, China.
⁶ The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
⁷ Qilu Regor Therapeutics, Inc., Shanghai, China.
⁸ University of Chinese Academy of Sciences, Beijing, China.
⁹ The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. dhyang@simm.ac.cn.
¹⁰ The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. dhyang@simm.ac.cn.
¹¹ University of Chinese Academy of Sciences, Beijing, China. dhyang@simm.ac.cn.
¹² The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. eric.xu@simm.ac.cn.
¹³ University of Chinese Academy of Sciences, Beijing, China. eric.xu@simm.ac.cn.
¹⁴ Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. zhang_yan@zju.edu.cn.
¹⁵ MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou, China. zhang_yan@zju.edu.cn.
¹⁶ Key Laboratory of Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou, China. zhang_yan@zju.edu.cn.
¹⁷ Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, Hangzhou, China. zhang_yan@zju.edu.cn.
¹⁸ School of Life Science and Technology, ShanghaiTech University, Shanghai, China. zhang_yan@zju.edu.cn.
¹⁹ School of Pharmacy, Fudan University, Shanghai, China. mwwang@simm.ac.cn.
²⁰ The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. mwwang@simm.ac.cn.
²¹ School of Basic Medical Sciences, Fudan University, Shanghai, China. mwwang@simm.ac.cn.
²² The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. mwwang@simm.ac.cn.
²³ University of Chinese Academy of Sciences, Beijing, China. mwwang@simm.ac.cn.
²⁴ School of Life Science and Technology, ShanghaiTech University, Shanghai, China. mwwang@simm.ac.cn.

^# Contributed equally.

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 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Binding Sites / physiology
CHO Cells
Cell Line
Cricetulus
Cryoelectron Microscopy
Diabetes Mellitus, Type 2 / drug therapy
Enzyme Activation / drug effects
Glucagon-Like Peptide 1 / analogs & derivatives*
Glucagon-Like Peptide 1 / metabolism
Glucagon-Like Peptide 1 / pharmacology*
Glucagon-Like Peptide-1 Receptor / agonists*
Glucagon-Like Peptide-1 Receptor / genetics
Glucagon-Like Peptide-1 Receptor / metabolism
Glucagon-Like Peptides / pharmacology
HEK293 Cells
Humans
Molecular Dynamics Simulation
Protein Conformation
Sf9 Cells
Spodoptera

Substances

Glucagon-Like Peptide-1 Receptor
semaglutide
Glucagon-Like Peptides
Glucagon-Like Peptide 1