Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-24058-z
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Funding
- National Natural Science Foundation of China [81872915, 82073904, 81922071, 81773792, 81973373, 21704064]
- National Science and Technology Major Project of China-Key New Drug Creation and Manufacturing Program [2018ZX09735-001, 2018ZX09711002-002-005]
- National Key Basic Research Program of China [2018YFA0507000, 2019YFA0508800]
- Shanghai Municipal Science and Technology Major Project [2019SHZDZX02]
- Ministry of Science and Technology of China Major Project [XDB08020303]
- Shanghai Municipal Science and Technology Commission [19ZR1467500]
- Zhejiang Province Science Fund for Distinguished Young Scholars [LR19H310001]
- Fundamental Research Funds for Central Universities [2019XZZX001-01-06]
- Novo Nordisk-CAS Research Fund [NNCAS-2017-1-CC]
- Young Innovator Association of CAS Enrollment
- SA-SIBS Scholarship Program
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This study reports the cryo-EM structures of GLP-1R bound to an ago-allosteric modulator, revealing how the modulator executes positive allosteric modulation by enhancing both agonist binding and G protein coupling.
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.
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