The role of the tryptophan-rich allosteric network and sodium egress in GPCR activation - PubMed
4 hours ago
- #NMR
- #GPCR
- #allostery
- The human adenosine A2A receptor (A2AR) is a key member of the GPCR family, targeted by many FDA-approved drugs.
- 19F NMR was used to study functional states via a CF3-tag on TM6 and 5-fluorotryptophan reporters, revealing dynamic and discrete ligand-dependent states.
- A universal toggle switch interfacing with a sodium binding pocket was identified, shared by over 560 GPCRs, indicating its fundamental role in activation.
- Computational rigidity-theory showed tryptophan reporters are located along allosteric activation pathways, highlighting their role in signal propagation.
- W2466.48, linked to the toggle switch, is crucial for regulating allosteric networks spanning from the orthosteric pocket to the Gβ interface and Gsα nucleotide pocket.
- Sodium concentration affects receptor conformation: high levels stabilize the inactive state, while low levels enhance the activation ensemble and precoupled state.
- Release of sodium from the conserved pocket, either basally or via agonist binding, enables sampling of the precoupled state necessary for activation and coupling.