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.