EMD-31329
Cryo-EM structure of the compound 2-bound human GLP-1 receptor-Gs complex
EMD-31329
Single-particle2.5 Å
Deposition: 21/05/2021Map released: 11/08/2021
Last modified: 13/11/2024
Sample Organism:
Homo sapiens,
synthetic construct,
Rattus norvegicus,
Bos taurus
Sample: Cryo-EM structure of the compound 2-bound human GLP-1 receptor-Gs complex
Fitted models: 7evm (Avg. Q-score: 0.481)
Deposition Authors: Cong Z, Chen L
Sample: Cryo-EM structure of the compound 2-bound human GLP-1 receptor-Gs complex
Fitted models: 7evm (Avg. Q-score: 0.481)
Deposition Authors: Cong Z, Chen L
Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor.
Cong Z,
Chen LN,
Ma H,
Zhou Q,
Zou X,
Ye C,
Dai A,
Liu Q 
,
Huang W ,
Sun X,
Wang X,
Xu P ,
Zhao L,
Xia T,
Zhong W,
Yang D ,
Eric Xu H ,
Zhang Y ,
Wang MW
(2021) Nat Commun , 12 , 3763 - 3763
,
Huang W ,
Sun X,
Wang X,
Xu P ,
Zhao L,
Xia T,
Zhong W,
Yang D ,
Eric Xu H ,
Zhang Y ,
Wang MW
(2021) Nat Commun , 12 , 3763 - 3763
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 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.