Allosteric Communication Mechanism in the Glucagon Receptor.

The glucagon receptor is dysregulated in metabolic disorders. Recent drug discovery has shown that agonists for the glucagon receptor might be more promising as therapeutics. Allosteric modulation may pave an alternative way to initiate responses that are required to target these metabolic disorders. Here, we investigated the allosteric communication mechanisms within the glucagon receptor using molecular dynamics simulations on five glucagon receptor states. Results highlighted that the extracellular domain is dynamic in the absence of an orthosteric agonist. In the presence of a partial agonist, we observed increased flexibility in the N-terminus of the receptor compared to the full agonist bound receptor. Class B GPCR microswitches showed repacking going from the inactive to the active state, allowing for G protein coupling. In the full agonist and G protein-bound state, Gαs showed both translational and rotational movement in the N-terminus, core and α5-helix, thereby forming key interactions between the core of the G protein and the glucagon receptor. Lastly, the allosteric communication from the extracellular region to the G protein coupling region of the glucagon receptor was the strongest in the intracellular negative allosteric modulator-bound state, the full agonist and G protein-bound state, and the full agonist-bound G protein-free state. The residue positions predicted to play a significant role in the allosteric communication mechanism showed overlap with disease associated mutations. Overall, our study provides insights into the allosteric communication mechanism in a class B GPCR which sets the foundation for future design of potential allosteric modulators targeting the glucagon receptor.