Structural Basis for Angiotensin II Type I Receptor G Protein-biased Signaling
- 1Harvard Medical School
Abstract
Biased agonism at the angiotensin II type 1 receptor (AT1R) offers a promising strategy for developing safer cardiovascular therapeutics. While beta-arrestin-biased agonism has been extensively investigated, G protein-biased signaling remains poorly understood. Here, we report structures of AT1R coupled to G protein and either the endogenous agonist angiotensin II (AngII) or the G protein-biased agonist TRV055. The ligands adopt similar overall poses, with coordinated rearrangements extending from the orthosteric pocket to the intracellular surface. The structures provide a detailed view of a TM7-centered microswitch network linking ligand recognition to G protein coupling. Functional analyses of peptide analogs identify the ligand's amino terminus as a key determinant of G protein bias, while mutagenesis of the microswitch network shifts AngII toward beta-arrestin-biased signaling and converts the G protein-biased agonist TRV055 into a beta-arrestin-biased ligand. These findings establish a framework for G protein-biased AT1R activation and provide mechanistic insight for the rational design of pathway-selective GPCR therapeutics.
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BibTeX
@misc{liu2026structural,
title = {{Structural Basis for Angiotensin II Type I Receptor G Protein-biased Signaling}},
author = {J. Liu and M. Skiba and A. Kruse},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.13.758900},
url = {https://www.biorxiv.org/content/10.64898/2026.10.13.758900v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Structural Basis for Angiotensin II Type I Receptor G Protein-biased Signaling
AU - J. Liu
AU - M. Skiba
AU - A. Kruse
PY - 2026
DA - 2026/10/13
PB - bioRxiv
DO - 10.64898/2026.10.13.758900
UR - https://www.biorxiv.org/content/10.64898/2026.10.13.758900v1
AB - Biased agonism at the angiotensin II type 1 receptor (AT1R) offers a promising strategy for developing safer cardiovascular therapeutics. While beta-arrestin-biased agonism has been extensively investigated, G protein-biased signaling remains poorly understood. Here, we report structures of AT1R coupled to G protein and either the endogenous agonist angiotensin II (AngII) or the G protein-biased agonist TRV055. The ligands adopt similar overall poses, with coordinated rearrangements extending from the orthosteric pocket to the intracellular surface. The structures provide a detailed view of a TM7-centered microswitch network linking ligand recognition to G protein coupling. Functional analyses of peptide analogs identify the ligand's amino terminus as a key determinant of G protein bias, while mutagenesis of the microswitch network shifts AngII toward beta-arrestin-biased signaling and converts the G protein-biased agonist TRV055 into a beta-arrestin-biased ligand. These findings establish a framework for G protein-biased AT1R activation and provide mechanistic insight for the rational design of pathway-selective GPCR therapeutics.
ER -