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

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...

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Published in:Nature communications 2021-06, Vol.12 (1), p.3763-3763, Article 3763
Main Authors: 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, Eric Xu, H., Zhang, Yan, Wang, Ming-Wei
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Language:English
Subjects:
101/28
13/109
13/95
631/154/436/2387
631/45/612/194
631/535/1258/1259
631/57/2266
82/29
82/80
82/81
82/83
Agonists
Allosteric properties
Binding sites
Chemical bonds
Coupling (molecular)
Diabetes mellitus (non-insulin dependent)
Electron microscopy
Glucagon
Glucagon-like peptide 1
Homeostasis
Humanities and Social Sciences
Metabolic disorders
Modulation
Modulators
multidisciplinary
Peptides
Receptors
Science
Science (multidisciplinary)
Side effects
Therapeutic targets
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container_title Nature communications
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creator Cong, Zhaotong
Chen, Li-Nan
Ma, Honglei
Zhou, Qingtong
Zou, Xinyu
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Dai, Antao
Liu, Qing
Huang, Wei
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Wang, Xi
Xu, Peiyu
Zhao, Lihua
Xia, Tian
Zhong, Wenge
Yang, Dehua
Eric Xu, H.
Zhang, Yan
Wang, Ming-Wei
description 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. 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 G s which offers insights into the molecular details of ago-allosterism.
doi_str_mv 10.1038/s41467-021-24058-z
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subjects 101/28
13/109
13/95
631/154/436/2387
631/45/612/194
631/535/1258/1259
631/57/2266
82/29
82/80
82/81
82/83
Agonists
Allosteric properties
Binding sites
Chemical bonds
Coupling (molecular)
Diabetes mellitus (non-insulin dependent)
Electron microscopy
Glucagon
Glucagon-like peptide 1
Homeostasis
Humanities and Social Sciences
Metabolic disorders
Modulation
Modulators
multidisciplinary
Peptides
Receptors
Science
Science (multidisciplinary)
Side effects
Therapeutic targets
title Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor
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