Structural insights into probe-dependent positive allosterism of the GLP-1 receptor.

Nature Chemical Biology
Ana B BuenoKyle W Sloop

Abstract

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 Gs. 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.

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Citations

Nov 13, 2020·Proceedings of the National Academy of Sciences of the United States of America·Takahiro KawaiKyle W Sloop
Mar 16, 2021·Journal of Medicinal Chemistry·Francis S WillardAna B Bueno
May 1, 2021·International Journal of Molecular Sciences·Mikołaj Mizera, Dorota Latek
Sep 28, 2021·ACS Chemical Biology·Jiang WangHuaiyu Yang
Aug 3, 2021·Molecular Pharmacology·Christopher T SzlenkSenthil Natesan

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Methods Mentioned

BETA
competition binding
saturation binding
size-exclusion chromatography
electron microscopy

Software Mentioned

MOE2018
Coot
MMPBSA
Gctf
Molprobity
PRISM
Phenix
MotionCor2

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