| Structural highlights
Publication Abstract from PubMed
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.
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 Nat Commun. 2021 Jun 18;12(1):3763. doi: 10.1038/s41467-021-24058-z. PMID:34145245[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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References
- ↑ 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. Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor. Nat Commun. 2021 Jun 18;12(1):3763. PMID:34145245 doi:10.1038/s41467-021-24058-z
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