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Peer-reviewedCC BY 4.0Nature Communications

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

  • Kevin M. Jude1,2,3
  • Carl-Mikael Suomivuori4
  • Deepa Waghray2
  • Shoji Maeda2
  • Yoshinori Fujiyoshi5
  • Asuka Inoue6,7
  • K. Christopher Garcia1,2,3
  • Naotaka Tsutsumi5
7 affiliations
  1. 1Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA USA
  2. 2Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA USA
  3. 3Department of Structural Biology, Stanford University School of Medicine, Stanford, CA USA
  4. 4Department of Pharmacology, Yale School of Medicine, New Haven, CT USA
  5. 5Cellular and Structural Physiology Laboratory, Institute of Integrated Research, Institute of Science Tokyo, Bunkyo, Tokyo Japan
  6. 6Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
  7. 7Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
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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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Cite

BibTeXRIS
BibTeX
@article{jude2026structural,
  title = {{Structural basis of stepwise G protein activation by the viral chemokine receptor US28}},
  author = {Kevin M. Jude and Carl-Mikael Suomivuori and Deepa Waghray and Shoji Maeda and Yoshinori Fujiyoshi and Asuka Inoue and K. Christopher Garcia and Naotaka Tsutsumi},
  journal = {Nature Communications},
  year = {2026},
  month = sep,
  doi = {10.1038/s41467-026-78122-7},
  url = {https://doi.org/10.1038/s41467-026-78122-7},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Structural basis of stepwise G protein activation by the viral chemokine receptor US28
AU  - Kevin M. Jude
AU  - Carl-Mikael Suomivuori
AU  - Deepa Waghray
AU  - Shoji Maeda
AU  - Yoshinori Fujiyoshi
AU  - Asuka Inoue
AU  - K. Christopher Garcia
AU  - Naotaka Tsutsumi
PY  - 2026
DA  - 2026/09/28
JO  - Nature Communications
DO  - 10.1038/s41467-026-78122-7
UR  - https://doi.org/10.1038/s41467-026-78122-7
AB  - 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.
SN  - 2041-1723
ER  -