Delineating the conformational landscape of the adenosine A2A receptor during G protein coupling Application note

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Delineating the conformational landscape of the adenosine A2A receptor during G protein coupling (PDF, 9 MB)

G-protein-coupled receptors (GPCRs) represent a ubiquitous membrane protein family and are important drug targets. Their diverse signaling pathways are driven by complex pharmacology arising from a conformational ensemble rarely captured by structural methods.

Here, fluorine nuclear magnetic resonance spectroscopy (¹⁹F NMR) is used to delineate key functional states of the adenosine A_2A receptor (A_2AR) complexed with heterotrimeric G protein (Gαsβ1γ2) in a phospholipid membrane milieu. Analysis of A_2AR spectra as a function of ligand, G protein, and nucleotide identifies an ensemble represented by inactive states, a G-protein-bound activation intermediate, and distinct nucleotide-free states associated with either partial- or full-agonist-driven activation. The Gβγ subunit is found to be critical in facilitating ligand-dependent allosteric transmission, as shown by ¹⁹F NMR, biochemical, and computational studies. The results provide a mechanistic basis for understanding basal signaling, efficacy, pre-coupling, and allostery in GPCRs.

Delineating the conformational landscape of the adenosine A2A receptor during G protein coupling Application note

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Delineating the conformational landscape of the adenosine A2A receptor during G protein coupling Application note

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