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TitleStructural insights into probe-dependent positive allosterism of the GLP-1 receptor.
Journal, issue, pagesNat Chem Biol, Vol. 16, Issue 10, Page 1105-1110, Year 2020
Publish dateJul 20, 2020
AuthorsAna B Bueno / Bingfa Sun / Francis S Willard / Dan Feng / Joseph D Ho / David B Wainscott / Aaron D Showalter / Michal Vieth / Qi Chen / Cynthia Stutsman / Betty Chau / James Ficorilli / Francisco J Agejas / Graham R Cumming / Alma Jiménez / Isabel Rojo / Tong Sun Kobilka / Brian K Kobilka / Kyle W Sloop /
PubMed AbstractDrugs that promote the association of protein complexes are an emerging therapeutic strategy. We report discovery of a G protein-coupled receptor (GPCR) ligand that stabilizes an active state ...Drugs that promote the association of protein complexes are an emerging therapeutic strategy. We report discovery of a G protein-coupled receptor (GPCR) ligand that stabilizes an active state conformation by cooperatively binding both the receptor and orthosteric ligand, thereby acting as a 'molecular glue'. LSN3160440 is a positive allosteric modulator of the GLP-1R optimized to increase the affinity and efficacy of GLP-1(9-36), a proteolytic product of GLP-1(7-36). The compound enhances insulin secretion in a glucose-, ligand- and GLP-1R-dependent manner. Cryo-electron microscopy determined the structure of the GLP-1R bound to LSN3160440 in complex with GLP-1 and heterotrimeric G. The modulator binds high in the helical bundle at an interface between TM1 and TM2, allowing access to the peptide ligand. Pharmacological characterization showed strong probe dependence of LSN3160440 for GLP-1(9-36) versus oxyntomodulin that is driven by a single residue. Our findings expand protein-protein modulation drug discovery to uncompetitive, active state stabilizers for peptide hormone receptors.
External linksNat Chem Biol / PubMed:32690941
MethodsEM (single particle)
Resolution3.3 Å
Structure data

21147

6vcb

EMDB-21147, PDB-6vcb:
Cryo-EM structure of the Glucagon-like peptide-1 receptor in complex with G protein, GLP-1 peptide and a positive allosteric modulator
Method: EM (single particle) / Resolution: 3.3 Å

Chemicals

ChemComp-QW7:
1-[(1R)-1-(2,6-dichloro-3-methoxyphenyl)ethyl]-6-{2-[(2R)-piperidin-2-yl]phenyl}-1H-benzimidazole

Source
  • homo sapiens (human)
  • lama glama (llama)
KeywordsSIGNALING PROTEIN/MEMBRANE PROTEIN / G protein-coupled receptor / membrane protein / family B GPCR / diabetes / allosteric modulator / SIGNALING PROTEIN-MEMBRANE PROTEIN complex

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