Structural basis of stepwise G protein activation by the viral chemokine receptor US28

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-G q 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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Publication Details

Journal
Nature Communications
Published
2026-09-28
DOI
https://doi.org/10.1038/s41467-026-78122-7
Primary Topic
Receptor Mechanisms and Signaling
Type
article
Field-Weighted Citation Impact
0.00

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article

Structural basis of stepwise G protein activation by the viral chemokine receptor US28

Kevin M. Jude, Shoji Maeda, K. Christopher García, Yoshinori Fujiyoshi et al.
Nature Communications
Receptor Mechanisms and Signaling
article

Structural basis of stepwise G protein activation by the viral chemokine receptor US28

Kevin M. Jude, Shoji Maeda, K. Christopher García, Yoshinori Fujiyoshi, Carl‐Mikael Suomivuori, Naotaka Tsutsumi, Asuka Inoue, Deepa Waghray
article en

Abstract

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-G q 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.

Nature Communications
Howard Hughes Medical Institute (US), Tohoku University (JP), Kyoto University (JP), Yale University (US), Stanford Medicine (US), Institute of Science Tokyo (JP), Stanford University (US)
Howard Hughes Medical Institute, Uehara Memorial Foundation, Japan Agency for Medical Research and Development, Ludwig Institute for Cancer Research, National Institutes of Health, Japan Society for the Promotion of Science, Japan Science and Technology Agency, National Institute of Allergy and Infectious Diseases
Decent work and economic growth
Openalex Percentile: Top 20%
Receptor Mechanisms and Signaling
DOIOpen Access PDFOpenAlex
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