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bioRxiv · 10.64898/2025.12.10.692789

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.
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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 multiple activation states of the US28-Gq complex. Using cryo-electron microscopy and an engineered chemokine superagonist, we determined three distinct complex structures, capturing a GDP-bound Encounter state, the nucleotide-free Canonical state, and a putative intermediate bridging the two states, the Transition-to-Canonical state. These structures, along with simulations and functional data, provide high-resolution snapshots of a plausible G protein activation trajectory and support a stepwise conformational model for G protein activation. This activation cascade closely parallels mechanisms proposed for human GPCRs, suggesting a conserved GPCR signaling mechanism.

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Jude, K. M., Suomivuori, C.-M., Waghray, D., Maeda, S., Fujiyoshi, Y., Inoue, A., Garcia, K. C., Tsutsumi, N.. 2025-12-10. Structural basis of stepwise G protein activation by a viral chemokine receptor. https://doi.org/10.64898/2025.12.10.692789

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