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TitleMolecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor.
Journal, issue, pagesNat Commun, Vol. 12, Issue 1, Page 3763, Year 2021
Publish dateJun 18, 2021
AuthorsZhaotong Cong / Li-Nan Chen / Honglei Ma / Qingtong Zhou / Xinyu Zou / Chenyu Ye / Antao Dai / Qing Liu / Wei Huang / Xianqiang Sun / Xi Wang / Peiyu Xu / Lihua Zhao / Tian Xia / Wenge Zhong / Dehua Yang / H Eric Xu / Yan Zhang / Ming-Wei Wang /
PubMed AbstractThe 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 ...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.
External linksNat Commun / PubMed:34145245 / PubMed Central
MethodsEM (single particle)
Resolution2.5 - 3.3 Å
Structure data

30866

7duq

EMDB-30866, PDB-7duq:
Cryo-EM structure of the compound 2 and GLP-1-bound human GLP-1 receptor-Gs complex
Method: EM (single particle) / Resolution: 2.5 Å

30867

7dur

EMDB-30867, PDB-7dur:
Cryo-EM structure of the compound 2-bound human GLP-1 receptor-Gs complex
Method: EM (single particle) / Resolution: 3.3 Å

30936

7e14

EMDB-30936: Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor
PDB-7e14: Compound2_GLP-1R_OWL833_Gs complex structure
Method: EM (single particle) / Resolution: 2.9 Å

31329

7evm

EMDB-31329, PDB-7evm:
Cryo-EM structure of the compound 2-bound human GLP-1 receptor-Gs complex
Method: EM (single particle) / Resolution: 2.5 Å

Chemicals

ChemComp-HNO:
N-tert-butyl-6,7-bis(chloranyl)quinoxalin-2-amine

ChemComp-CLR:
CHOLESTEROL

ChemComp-V6G:
3-[(1S,2S)-1-(5-[(4S)-2,2-dimethyloxan-4-yl]-2-{(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carbonyl}-1H-indol-1-yl)-2-methylcyclopropyl]-1,2,4-oxadiazol-5(4H)-one

Source
  • homo sapiens (human)
  • synthetic construct (others)
  • rattus norvegicus (Norway rat)
  • bos taurus (cattle)
KeywordsBIOSYNTHETIC PROTEIN / Glucagon-like peptide-1 receptor / Glucagon-like peptide-1 / Ago-allosteric modulator / Type 2 diabetes / Compound 2 / Class B GPCR / MEMBRANE PROTEIN / ago-allosteric modulation of GLP-1R / STRUCTURAL PROTEIN

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