From Structure to Dynamics: Activation Mechanism of the G Protein-Coupled Bile Acid Receptor 1-Gs Complex

The G protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5) is a key mediator of bile acid signaling, exerting its physiological effects through coupling with the stimulatory G protein (Gs). This interaction is essential for stabilizing the receptors active conformation and triggering downstream signaling. Among endogenous ligands, lithocholic acid (LCA) is the most potent natural agonist. However, the dynamic features underlying its binding and activation mechanisms remain poorly defined. In this study, we investigated the molecular basis of the interaction between LCA and GPBAR1, as well as the functional consequences of this interaction on receptor activation by integrating homology modelling, molecular docking, and molecular dynamics (MD) simulations. Our calculations reveal that LCA binding stabilizes the active state of GPBAR1, biasing the conformational ensemble of TM5 and TM6, as well as the main microswitches. These ligand-induced rearrangements enhance the coupling interface with the 5 helix of Gs and facilitate allosteric communication between the orthosteric and intracellular sites. Overall, our findings provide dynamic insight into how LCA modulates GPBAR1 activation and G protein engagement, highlighting its role as a molecular effector in bile acid signaling, and furnishing molecular detail relevant to ongoing efforts in GPBAR1-targeted compound development.