Distinct conformational dynamics of the type-2 Angiotensin II receptor bound to Angiotensin II and Angiotensin (1–7)
4 affiliations
- 1Department of Biophysics, Faculty of Medicine, Erzincan Binali Yildirim University
- 2Department of Medical Biochemistry, Akdeniz University Medical School
- 3Department of Mathematics and Science Education, Akdeniz University
- 4Department of Biophysics, Akdeniz University Medical School
Abstract
The Angiotensin II type-2 receptor (AGTR2) is a G protein-coupled receptor (GPCR) that mediates vasodilatory, anti-proliferative, and cardioprotective responses as part of the renin–angiotensin system (RAS). However, the precise structural dynamics underlying its ligand-specific activation remain incompletely understood. In this study, we performed long-timescale molecular dynamics (MD) simulations to investigate how Angiotensin peptides differentially modulate the structural dynamics of AGTR2 in both inactive- and active-like conformations and to elucidate ligand-specific modulation of AGTR2 in the RAS protective arm. Ang II stabilized a ‘Locked Active State’ through compact TM3–TM6 distances, persistent hydrogen bonding (PHE8–LYS2155.42), salt bridges (ARG2-ASP2796.58, ARG2-ASP2977.32), hydrophobic contacts (TRP1002.60, MET1283.36), and rotameric locking of micro-switches. These interactions stabilized Helix 8, enhancing dynamic network connectivity and supporting ligand-dependent activation-related conformational tendencies rather than a full canonical GPCR activation transition. Conversely, Ang1–7 induced a ‘Flexible Intermediate State’ characterized by weaker interactions (PRO7–THR1253.33), dynamic instability at the Helix 8 interface, and increased conformational sampling. Activation motif analyses (CWxP, PIF, E/DRY, NPxxY), DCC maps, CP, DRIN metrics, and PCA confirmed distinct signaling features for each ligand. This study provides a dual functional profile for AGTR2, where Ang II acts as a strong conformational stabilizer promoting activation-related dynamic features, while Ang 1–7 serves as a dynamic modulator. These findings contribute to a structural and dynamic framework for understanding AGTR2 signaling and supporting its therapeutic potential in fine-tuning cardiovascular responses within the RAS.
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BibTeX
@article{yasar2026distinct,
title = {{Distinct conformational dynamics of the type-2 Angiotensin II receptor bound to Angiotensin II and Angiotensin (1–7)}},
author = {Ekrem Yasar and Segun Dogru and Erol Eroglu and Nazmi Yaras},
journal = {Scientific Reports},
year = {2026},
month = jul,
doi = {10.1038/s41598-026-40510-w},
url = {https://doi.org/10.1038/s41598-026-40510-w},
note = {CC BY},
}
RIS
TY - JOUR
TI - Distinct conformational dynamics of the type-2 Angiotensin II receptor bound to Angiotensin II and Angiotensin (1–7)
AU - Ekrem Yasar
AU - Segun Dogru
AU - Erol Eroglu
AU - Nazmi Yaras
PY - 2026
DA - 2026/07/01
JO - Scientific Reports
DO - 10.1038/s41598-026-40510-w
UR - https://doi.org/10.1038/s41598-026-40510-w
AB - The Angiotensin II type-2 receptor (AGTR2) is a G protein-coupled receptor (GPCR) that mediates vasodilatory, anti-proliferative, and cardioprotective responses as part of the renin–angiotensin system (RAS). However, the precise structural dynamics underlying its ligand-specific activation remain incompletely understood. In this study, we performed long-timescale molecular dynamics (MD) simulations to investigate how Angiotensin peptides differentially modulate the structural dynamics of AGTR2 in both inactive- and active-like conformations and to elucidate ligand-specific modulation of AGTR2 in the RAS protective arm. Ang II stabilized a ‘Locked Active State’ through compact TM3–TM6 distances, persistent hydrogen bonding (PHE8–LYS2155.42), salt bridges (ARG2-ASP2796.58, ARG2-ASP2977.32), hydrophobic contacts (TRP1002.60, MET1283.36), and rotameric locking of micro-switches. These interactions stabilized Helix 8, enhancing dynamic network connectivity and supporting ligand-dependent activation-related conformational tendencies rather than a full canonical GPCR activation transition. Conversely, Ang1–7 induced a ‘Flexible Intermediate State’ characterized by weaker interactions (PRO7–THR1253.33), dynamic instability at the Helix 8 interface, and increased conformational sampling. Activation motif analyses (CWxP, PIF, E/DRY, NPxxY), DCC maps, CP, DRIN metrics, and PCA confirmed distinct signaling features for each ligand. This study provides a dual functional profile for AGTR2, where Ang II acts as a strong conformational stabilizer promoting activation-related dynamic features, while Ang 1–7 serves as a dynamic modulator. These findings contribute to a structural and dynamic framework for understanding AGTR2 signaling and supporting its therapeutic potential in fine-tuning cardiovascular responses within the RAS.
SN - 2045-2322
ER -