Structural Insight into Ligand Binding and Activation of the Orphan GPCR Mas1

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 W6.48 toggle switch engagement, Mas1 adopts a non-canonical activation strategy driven by a ligand-induced hydrophobic compression plane involving

SUBMITTER: Yumu Zhang 

PROVIDER: S-SCDT-10_1038-S44318-026-00764-6 | biostudies-other |

REPOSITORIES: biostudies-other