Allosteric modulation of class B1 GPCRs via cholesterol binding sites

Class B1 GPCRs are key targets for prevalent diseases, but existing peptide drugs targeting these receptors have limitations that urge the development of novel small molecules, particularly of allosteric modulators with greater potential to fine-tune receptor outputs. GPCR-cholesterol binding sites represent a large, untapped opportunity for allosteric drug development.

However, they remain largely intractable due to poor understanding of site architectures related to challenges with their computational, structural, and functional modelling.

Here, we present novel in silico predictions of cholesterol binding sites on two class B1 GPCRs, the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR), with critical roles in glucose and energy homeostasis, and major targets for obesity-associated metabolic diseases.

We also present evidence on the functional effects of mutating a predicted GLP-1R-cholesterol binding site residue, demonstrating the potential to modulate receptor outputs by modifying receptor-cholesterol interactions.

We hereby propose to use a multidisciplinary approach encompassing cutting-edge techniques and emerging methodologies to fully resolve the locations and functional significance of cholesterol binding sites on both receptors.

Our project will produce fundamental new knowledge of great value for future design of better GLP-1R/GCGR-targeting drugs to treat diseases such as obesity, type 2 diabetes, and metabolic associated fatty liver disease.