Cryo-EM structures of the Mas1 receptor bound to NPFF and AR234958 revealed a conserved hydrophobic binding pocket and a non-canonical activation mechanism driven by a hydrophobic compression plane.
Elucidating the cryo-EM structures of the Mas1 receptor provides a structural framework for understanding its non-canonical activation and enables rational design of selective cardiovascular therapeutics.
Abstract 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.
Zhang et al. (Mon,) reported a other. NPFF and AR234958 was evaluated. Cryo-EM structures of the Mas1 receptor bound to NPFF and AR234958 revealed a conserved hydrophobic binding pocket and a non-canonical activation mechanism driven by a hydrophobic compression plane.