Structural basis of stepwise G protein activation by a viral chemokine receptor
Jude, K. M.; Suomivuori, C.-M.; Waghray, D.; Maeda, S.; Fujiyoshi, Y.; Inoue, A.; Garcia, K. C.; Tsutsumi, N.
Show abstract
G protein-coupled receptors (GPCRs) govern diverse cellular responses and are crucial drug targets. However, the sequence of structural events from G protein recognition to GDP release has remained elusive. Here, we leveraged the viral chemokine GPCR US28 to capture transient activation states of the US28-Gq complex. Using cryo-electron microscopy and an engineered chemokine superagonist, we determined three distinct complex structures, capturing the initial GDP-bound TL-state, the nucleotide-free C-state, and a previously unobserved intermediate bridging the two states, the T2C-state. These structures, along with simulations and functional data, provide high-resolution snapshots of the G protein activation trajectory and reveal a stepwise conformational mechanism that orchestrates G protein activation. This activation cascade closely parallels mechanisms proposed for human GPCRs, suggesting a conserved GPCR signaling mechanism.
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