<p>The Mas1 receptor, an orphan class A G-protein-coupled receptor (GPCR), plays pivotal roles in cardiovascular and anti-inflammatory regulation. Despite its therapeutic relevance, the structural mechanisms underlying Mas1 ligand binding and activation remain poorly understood. Here, we report cryo-EM structures of Mas1 bound to two chemically distinct agonists—neuropeptide FF (NPFF) and synthetic small-molecule AR234958—captured in complex with inhibitory G proteins. These structures reveal a conserved orthosteric binding pocket accommodating both ligands through shared hydrophobic interactions. Unlike many other class A GPCRs that rely on direct W^6.48 toggle switch engagement, Mas1 adopts a non-canonical activation strategy driven by a ligand-induced hydrophobic compression plane involving residues Y248^6.55, L87^2.60, I84^2.57, and L266^7.39 at the bottom of the ligand binding pocket. This mechanism transmits mechanical tension to promote TM6 displacement and G protein coupling. Functional mutagenesis validates this model, identifying two transmembrane helix 6 (TM6) residues, M244^6.51 and F237^6.44, as critical molecular switches. Comparative analyses of Mas1-related receptors, MRGPRX1–X4, reveal conserved features and mechanistic divergence within this subfamily. These findings provide a structural framework for understanding Mas1 pharmacology and rational design of selective therapeutics.</p>