7E14
Compound2_GLP-1R_OWL833_Gs complex structure
Summary for 7E14
| Entry DOI | 10.2210/pdb7e14/pdb |
| EMDB information | 30936 |
| Descriptor | Gs, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, G protein, ... (8 entities in total) |
| Functional Keywords | ago-allosteric modulation of glp-1r, membrane protein |
| Biological source | Homo sapiens More |
| Total number of polymer chains | 5 |
| Total formula weight | 142599.17 |
| Authors | Cong, Z.T.,Chen, L.N.,Ma, H.L.,Yang, D.H.,Xu, H.E.,Zhang, Y.,Wang, M.W. (deposition date: 2021-01-30, release date: 2021-07-07, Last modification date: 2024-03-27) |
| 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 Cited by 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: 34145245DOI: 10.1038/s41467-021-24058-z PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.9 Å) |
Structure validation
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