7DUR

Cryo-EM structure of the compound 2-bound human GLP-1 receptor-Gs complex

Summary for 7DUR

• Entry DOI: 10.2210/pdb7dur/pdb
• EMDB information: 30867
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (7 entities in total)
• Functional Keywords: glucagon-like peptide-1 receptor, ago-allosteric modulator, type 2 diabetes, compound 2, class b gpcr, biosynthetic protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 5
• Total formula weight: 160122.78

Authors

Cong, Z.,Chen, L.,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.,Xu, H.E.,Zhang, Y.,Wang, M. (deposition date: 2021-01-11, release date: 2021-08-11, Last modification date: 2024-10-16)

Primary citation

Cong, Z.,Chen, L.N.,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, M.W.
Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor.
Nat Commun, 12:3763-3763, 2021

PubMed 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. 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.

PubMed: 34145245
DOI: 10.1038/s41467-021-24058-z

Experimental method

ELECTRON MICROSCOPY (3.3 Å)