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TitleDifferential GLP-1R Binding and Activation by Peptide and Non-peptide Agonists.
Journal, issue, pagesMol Cell, Vol. 80, Issue 3, Page 485-500.e7, Year 2020
Publish dateNov 5, 2020
AuthorsXin Zhang / Matthew J Belousoff / Peishen Zhao / Albert J Kooistra / Tin T Truong / Sheng Yu Ang / Christina Rye Underwood / Thomas Egebjerg / Petr Šenel / Gregory D Stewart / Yi-Lynn Liang / Alisa Glukhova / Hari Venugopal / Arthur Christopoulos / Sebastian G B Furness / Laurence J Miller / Steffen Reedtz-Runge / Christopher J Langmead / David E Gloriam / Radostin Danev / Patrick M Sexton / Denise Wootten /
PubMed AbstractPeptide drugs targeting class B1 G-protein-coupled receptors (GPCRs) can treat multiple diseases; however, there remains substantial interest in the development of orally delivered non-peptide drugs. ...Peptide drugs targeting class B1 G-protein-coupled receptors (GPCRs) can treat multiple diseases; however, there remains substantial interest in the development of orally delivered non-peptide drugs. Here, we reveal unexpected overlap between signaling and regulation of the glucagon-like peptide-1 (GLP-1) receptor by the non-peptide agonist PF 06882961 and GLP-1 that was not observed for another compound, CHU-128. Compounds from these patent series, including PF 06882961, are currently in clinical trials for treatment of type 2 diabetes. High-resolution cryoelectron microscopy (cryo-EM) structures reveal that the binding sites for PF 06882961 and GLP-1 substantially overlap, whereas CHU-128 adopts a unique binding mode with a more open receptor conformation at the extracellular face. Structural differences involving extensive water-mediated hydrogen bond networks could be correlated to functional data to understand how PF 06882961, but not CHU-128, can closely mimic the pharmacological properties of GLP-1. These findings will facilitate rational structure-based discovery of non-peptide agonists targeting class B GPCRs.
External linksMol Cell / PubMed:33027691
MethodsEM (single particle)
Resolution2.1 - 2.5 Å
Structure data

21992

6x18

EMDB-21992, PDB-6x18:
GLP-1 peptide hormone bound to Glucagon-Like peptide-1 (GLP-1) Receptor
Method: EM (single particle) / Resolution: 2.1 Å

21993

6x19

EMDB-21993, PDB-6x19:
Non peptide agonist CHU-128, bound to Glucagon-Like peptide-1 (GLP-1) Receptor
Method: EM (single particle) / Resolution: 2.1 Å

21994

6x1a

EMDB-21994, PDB-6x1a:
Non peptide agonist PF-06882961, bound to Glucagon-Like peptide-1 (GLP-1) Receptor
Method: EM (single particle) / Resolution: 2.5 Å

Chemicals

ChemComp-HOH:
WATER / Water

ChemComp-UK1:
3-{(1S)-1-[5-(2,2-dimethylmorpholin-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]butyl}-1,2,4-oxadiazol-5(4H)-one

ChemComp-UK4:
2-[(4-{6-[(4-cyano-2-fluorophenyl)methoxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid

Source
  • homo sapiens (human)
  • lama glama (llama)
KeywordsMEMBRANE PROTEIN / G-coupled protein receptor / GPCR / non-peptide agonist

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