Allosteric Modulators Enhancing GLP‑1 Binding to GLP-1R via a Transmembrane Site

The
glucagon-like peptide-1 receptor (GLP-1R) is a well-established
drug target for the treatment of type II diabetes. The development
of small-molecule positive allosteric modulators (PAMs) of GLP-1R
is a promising therapeutic strategy. Here, we report the discovery
and characterization of PAMs with distinct chemotypes, binding to
a cryptic pocket formed by the cytoplasmic half of TM3, TM5, and TM6.
Molecular dynamic simulations and mutagenesis studies indicate that
the PAM enlarges the orthosteric pocket to facilitate GLP-1 binding.
Further signaling assays characterized their probe-dependent signaling
profiles. Our findings provide mechanistic insights into fine-tuning
GLP-1R via this allosteric pocket and open up new avenues to design
small-molecule drugs for class B G-protein-coupled receptors.