Molecular Determinants of G Protein Subtype-Specific Coupling to the Angiotensin II Type 1 Receptor
- 1Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, United States
Abstract
Many G protein-coupled receptors (GPCRs) are capable of activating multiple heterotrimeric G protein subtypes. The angiotensin II type 1 receptor (AT1R) couples to both Gq and Gi family members, and the two families mediate distinct aspects of the effects of angiotensin II (AngII) on blood pressure and fluid balance. Previous work has pointed to fundamental differences in the strength and ligand-dependence of Gq versus Gi activation by AT1R. Here we resolve key aspects of the mechanisms underlying these subtype-specific patterns of G protein coupling to AT1R. Using cellular biosensors, we show that AT1R activates Gq more efficaciously than Gi. Leveraging mini-G proteins, engineered versions of G subunits that diverge only in the C-terminal 5 helix, we identify four residues dispersed throughout the 5 helix that are sufficient to account for these differences. We employ radioligand binding to demonstrate that subtype-specific differences originate at the level of allosteric coupling between ligand and transducer binding, and we use Systematic Protein Affinity Strength Modulation biosensors to show that Gq-specific residues in the 5 helix increase affinity for AngII-activated AT1R. We provide evidence that the 5 helix residue with the greatest effect on coupling makes interactions with AT1R intracellular loop 3 that were not resolved in a previously reported AT1R-Gq cryo-electron microscopy structure. These findings enhance our understanding of how AT1R differentially activates Gq and Gi and may ultimately guide pharmacological approaches to modulate certain G proteins downstream of AT1R and other GPCRs.
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BibTeX
@misc{acheampong2026molecular,
title = {{Molecular Determinants of G Protein Subtype-Specific Coupling to the Angiotensin II Type 1 Receptor}},
author = {A. A. Acheampong and M. K. Collins and A. R. Keller and A. P. Feld and B. M. Small and M. Ritt and C.-M. Suomivuori and S. Sivaramakrishnan and L. M. Wingler},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.30.755740},
url = {https://www.biorxiv.org/content/10.64898/2026.09.30.755740v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Molecular Determinants of G Protein Subtype-Specific Coupling to the Angiotensin II Type 1 Receptor
AU - A. A. Acheampong
AU - M. K. Collins
AU - A. R. Keller
AU - A. P. Feld
AU - B. M. Small
AU - M. Ritt
AU - C.-M. Suomivuori
AU - S. Sivaramakrishnan
AU - L. M. Wingler
PY - 2026
DA - 2026/09/30
PB - bioRxiv
DO - 10.64898/2026.09.30.755740
UR - https://www.biorxiv.org/content/10.64898/2026.09.30.755740v1
AB - Many G protein-coupled receptors (GPCRs) are capable of activating multiple heterotrimeric G protein subtypes. The angiotensin II type 1 receptor (AT1R) couples to both Gq and Gi family members, and the two families mediate distinct aspects of the effects of angiotensin II (AngII) on blood pressure and fluid balance. Previous work has pointed to fundamental differences in the strength and ligand-dependence of Gq versus Gi activation by AT1R. Here we resolve key aspects of the mechanisms underlying these subtype-specific patterns of G protein coupling to AT1R. Using cellular biosensors, we show that AT1R activates Gq more efficaciously than Gi. Leveraging mini-G proteins, engineered versions of G subunits that diverge only in the C-terminal 5 helix, we identify four residues dispersed throughout the 5 helix that are sufficient to account for these differences. We employ radioligand binding to demonstrate that subtype-specific differences originate at the level of allosteric coupling between ligand and transducer binding, and we use Systematic Protein Affinity Strength Modulation biosensors to show that Gq-specific residues in the 5 helix increase affinity for AngII-activated AT1R. We provide evidence that the 5 helix residue with the greatest effect on coupling makes interactions with AT1R intracellular loop 3 that were not resolved in a previously reported AT1R-Gq cryo-electron microscopy structure. These findings enhance our understanding of how AT1R differentially activates Gq and Gi and may ultimately guide pharmacological approaches to modulate certain G proteins downstream of AT1R and other GPCRs.
ER -