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<p>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&#xa0;‘Locked Active State’&#xa0;through compact TM3–TM6 distances, persistent hydrogen bonding (PHE8–LYS215<sup>5.42</sup>), salt bridges (ARG2-ASP279<sup>6.58</sup>, ARG2-ASP297<sup>7.32</sup>), hydrophobic contacts (TRP100<sup>2.60</sup>, MET128<sup>3.36</sup>), 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&#xa0;‘Flexible Intermediate State’ characterized by weaker interactions (PRO7–THR125<sup>3.33</sup>), 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,&#xa0;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.</p>

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Distinct conformational dynamics of the type-2 Angiotensin II receptor bound to Angiotensin II and Angiotensin (1–7)

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月20日

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  • Ekrem Yasar,
  • Segun Dogru,
  • Erol Eroglu,
  • Nazmi Yaras

摘要

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.