Mechanistic insights into G-protein coupling with an agonist-bound G-protein-coupled receptor
Research output: Contribution to journal › Journal article › Research › peer-review
G-protein-coupled receptors (GPCRs) activate heterotrimeric G proteins by promoting guanine nucleotide exchange. Here, we investigate the coupling of G proteins with GPCRs and describe the events that ultimately lead to the ejection of GDP from its binding pocket in the Gα subunit, the rate-limiting step during G-protein activation. Using molecular dynamics simulations, we investigate the temporal progression of structural rearrangements of GDP-bound Gs protein (Gs·GDP; hereafter GsGDP) upon coupling to the β2-adrenergic receptor (β2AR) in atomic detail. The binding of GsGDP to the β2AR is followed by long-range allosteric effects that significantly reduce the energy needed for GDP release: the opening of α1-αF helices, the displacement of the αG helix and the opening of the α-helical domain. Signal propagation to the Gs occurs through an extended receptor interface, including a lysine-rich motif at the intracellular end of a kinked transmembrane helix 6, which was confirmed by site-directed mutagenesis and functional assays. From this β2AR–GsGDP intermediate, Gs undergoes an in-plane rotation along the receptor axis to approach the β2AR–Gsempty state. The simulations shed light on how the structural elements at the receptor–G-protein interface may interact to transmit the signal over 30 Å to the nucleotide-binding site. Our analysis extends the current limited view of nucleotide-free snapshots to include additional states and structural features responsible for signaling and G-protein coupling specificity.
Original language | English |
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Journal | Nature Structural and Molecular Biology |
ISSN | 1545-9993 |
DOIs | |
Publication status | Accepted/In press - 2024 |
Bibliographical note
Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.
ID: 395081035