Multicolored sequential resonance energy transfer for detection of simultaneous ligand binding at G protein-coupled receptors

Alice Valentini, Bethany Dibnah, Marija Ciba, Elaine M. Duncan, Asmita Manandhar, Bethany Strellis, Luca Vita, Olivia Lucianno, Conor Massey, Sophie Coe, Trond Ulven, Brian D. Hudson () and Elisabeth Rexen Ulven ()
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Alice Valentini: University of Copenhagen
Bethany Dibnah: University of Glasgow
Marija Ciba: University of Copenhagen
Elaine M. Duncan: University of Glasgow
Asmita Manandhar: University of Copenhagen
Bethany Strellis: University of Glasgow
Luca Vita: University of Glasgow
Olivia Lucianno: University of Glasgow
Conor Massey: University of Glasgow
Sophie Coe: University of Glasgow
Trond Ulven: University of Copenhagen
Brian D. Hudson: University of Glasgow
Elisabeth Rexen Ulven: University of Copenhagen

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract G protein coupled-receptors (GPCRs) are the largest family of signalling proteins and highly successful drug targets. Most GPCR targeting drugs interact with a binding pocket for the natural ligand of the receptor, typically near the extracellular region of the transmembrane domains. Advancements in structural biology have identified additional allosteric binding sites in other parts of these receptors. Allosteric sites provide theoretical advantages, including the ability to modulate natural ligand function, and there is a need for better ways to study how ligands interact with these different GPCR binding sites. Here we have developed an approach to study multiple ligands binding to the same GPCR at the same time based on sequential resonance energy transfer between two fluorescent ligands. We use this approach to define ligand pharmacology and to understand binding kinetics at the FFA1 free fatty acid receptor, a clinically relevant receptor. This approach to study GPCR ligand interactions will aid development of new GPCR drugs.

Date: 2025
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DOI: 10.1038/s41467-025-61690-5

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