Allosteric pathways govern Gα protein coupling selectivity at promiscuous GPCRs
- 1Research Institute of the McGill University Health Centre
Abstract
G protein-coupled receptors (GPCRs) regulate diverse physiological responses by engaging distinct heterotrimeric G proteins, yet the basis of G selectivity in promiscuous receptors remains unclear. Although ligand bias holds therapeutic promise, selectivity has been assumed to reside mainly in the ligand-binding site (LBS) or G protein interface (GPI). Here, we combine whole-receptor mutagenesis, functional G protein assays, molecular dynamics simulations, interpretable machine learning method, and Bayesian network modeling to identify residue networks governing Gq/11 and G12/13 coupling and to define the molecular basis of G protein preference and promiscuity at two vasopressor GPCRs, the angiotensin II type 1 and prostaglandin F2 receptors. While residues within the LBS and GPI domains contribute to coupling efficiency and subtype discrimination, we find that long-range allosteric communication across the receptor, including from structurally unresolved domains, is the principal determinant of G protein preference and promiscuity. These allosteric pathways integrate multiple receptor domains, confer signaling robustness to mutation, and hierarchically govern coupling preferences. Our findings suggest that G protein selectivity is an allosterically encoded property of GPCRs and provide a conceptual framework for designing ligands and receptors with tailored G protein-biased signaling.
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BibTeX
@misc{boora2026allosteric,
title = {{Allosteric pathways govern Gα protein coupling selectivity at promiscuous GPCRs}},
author = {T. S. Boora and H. Chen and A. Cho and W. J. C. van der Velden and Y. Namkung and Y. Cao and J. Y. Paranjpe and F. M. Heydenreich and A. S. RODIN and S. Branciamore and N. Vaidehi and S. Laporte},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.28.747882},
url = {https://www.biorxiv.org/content/10.64898/2026.08.28.747882v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Allosteric pathways govern Gα protein coupling selectivity at promiscuous GPCRs
AU - T. S. Boora
AU - H. Chen
AU - A. Cho
AU - W. J. C. van der Velden
AU - Y. Namkung
AU - Y. Cao
AU - J. Y. Paranjpe
AU - F. M. Heydenreich
AU - A. S. RODIN
AU - S. Branciamore
AU - N. Vaidehi
AU - S. Laporte
PY - 2026
DA - 2026/08/28
PB - bioRxiv
DO - 10.64898/2026.08.28.747882
UR - https://www.biorxiv.org/content/10.64898/2026.08.28.747882v1
AB - G protein-coupled receptors (GPCRs) regulate diverse physiological responses by engaging distinct heterotrimeric G proteins, yet the basis of G selectivity in promiscuous receptors remains unclear. Although ligand bias holds therapeutic promise, selectivity has been assumed to reside mainly in the ligand-binding site (LBS) or G protein interface (GPI). Here, we combine whole-receptor mutagenesis, functional G protein assays, molecular dynamics simulations, interpretable machine learning method, and Bayesian network modeling to identify residue networks governing Gq/11 and G12/13 coupling and to define the molecular basis of G protein preference and promiscuity at two vasopressor GPCRs, the angiotensin II type 1 and prostaglandin F2 receptors. While residues within the LBS and GPI domains contribute to coupling efficiency and subtype discrimination, we find that long-range allosteric communication across the receptor, including from structurally unresolved domains, is the principal determinant of G protein preference and promiscuity. These allosteric pathways integrate multiple receptor domains, confer signaling robustness to mutation, and hierarchically govern coupling preferences. Our findings suggest that G protein selectivity is an allosterically encoded property of GPCRs and provide a conceptual framework for designing ligands and receptors with tailored G protein-biased signaling.
ER -