9x40 | pdb_00009x40

AR234958 bound Mas1 Receptor Complex

spinqualitylabelsall models 9x40, resolution 3.07Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9x40 is a 5 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.07Å Ligands: A1MCH Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GBB1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction. Publication Abstract from PubMed 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. Structural insight into ligand binding and activation of the orphan GPCR Mas1.,Zhang Y, Wang Q, Liu H, Shan H, Gu Y, Yang J, Gao Y, Wu K, Yang D, Xu HE EMBO J. 2026 Mar 30. doi: 10.1038/s44318-026-00764-6. PMID:41912627 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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