Angiotensin 1–7 Modulates the Dynamics and Activation of the Proto-Oncogene Mas Receptor

The proto-oncogene Mas receptor (MasR) is a class-A (orphan-type) G protein-coupled receptor (GPCR) that mediates the cardioprotective effects of Angiotensin 1–7 (Ang 1–7) within the renin–angiotensin system (RAS). Despite its therapeutic relevance, the molecular mechanisms underlying MasR activation remain elusive due to the lack of experimental structural data. In this study, we combined 1-μs all-atom molecular dynamics (MD) simulations of AlphaFold-modeled MasR with energetic network analyses to elucidate ligand-induced activation dynamics. Our results challenge the conventional electrostatic clamp model, revealing a distinct active anchor mechanism. We demonstrate that Ang 1–7 releases the inactive core lock (ARG245–TYR248) to engage a critical anchor cluster (SER109/PHE112). This interaction stabilizes a unique decoupled conformational state: while the NPxxY motif is fully activated and the intracellular vestibule expands via noncanonical communication hubs that substitute for the absent conserved microswitches, TM6 remains in a restricted, compact conformation (~10 Å). Thermodynamically, this partial activation is supported by favorable computed binding energetics and enhanced conformational plasticity. These findings provide a structural rationale for the partial agonist profile of Ang 1–7 and offer a transformative mechanistic framework for therapeutic targeting of the ACE2/Ang 1–7/MasR axis. We propose that rational drug design need not aim for maximal receptor opening; instead, strategies focusing on peptidomimetics or positive allosteric modulators (PAMs) that stabilize this specific compact active state could selectively potentiate protective RAS signaling. © 2026 John Wiley & Sons Ltd.