G protein-coupled receptors (GPCRs) are the therapeutically most important family of receptors in the human genome. GPCRs function through dynamic equilibria between multiple conformations, influenced by many factors, such as orthosteric ligands, pressure, and lipid environment.
In my postdoctoral research, I demonstrated that hydrostatic pressure shifts the β1-adrenergic receptor (β1AR) from a mixture of inactive and active states to a fully active state (1). This transition indicates that the active conformation has a smaller molar volume than the inactive conformation due to the collapse of empty cavities. By filling these cavities with cholesterol, I found that the receptor’s inactive state is stabilized, preventing activation of conserved GPCR microswitches (2). These voids in GPCRs represent potential allosteric hotspots, offering new avenues for developing more selective drugs.
A major focus of my current work is the selective activation of specific signaling pathways, or biased signaling, which is a promising approach in GPCR-targeted drug development. Using extensive NMR spectroscopy, I uncovered that arrestin can dynamically couple with both inactive and active GPCR conformations—a capacity not captured by static structures (3). This underlies arrestin’s promiscuous recognition of diverse GPCRs and elucidates the mechanism of arrestin-biased agonism exhibited by carvedilol. This widely used beta-blocker stabilizes a GPCR conformation that prevents G protein binding while still enabling arrestin engagement. These findings provide crucial molecular insights into how GPCRs selectively activate distinct cellular pathways, offering valuable implications for the design of targeted therapeutics.

[1] Abiko, L. A., Grahl, A. & Grzesiek, S. High Pressure Shifts the β1-Adrenergic Receptor to the Active Conformation in the Absence of G Protein. J. Am. Chem. Soc. 141, 16663–16670 (2019).
[2] Abiko, L. A., Teixeira, R. D., Engilberge, S., Grahl, A., Mühlethaler, T., Sharpe, T., Grzesiek, S. Filling of a water-free void explains the allosteric regulation of the β1-adrenergic receptor by cholesterol. Nat. Chem. 14, 1133–1141 (2022).
[3] Abiko, L. A., Petrovic, I., Tatli, M., Stahlberg, H., Grzesiek, S. Molecular mechanism of the β1-adrenergic receptor-biased signaling. bioRxiv 2024.07.19.604263.

Invited by: Laurent Catoire