25IL

Cryo-EM structure of MasR(del2-25)-Gq

Summary for 25IL

• Entry DOI: 10.2210/pdb25il/pdb
• EMDB information: 80138
• Descriptor: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, Soluble cytochrome b562,Proto-oncogene Mas,LgBiT tag, ... (5 entities in total)
• Functional Keywords: gpcr, signaling protein, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 172074.49

Authors

Suzuki, S.,Nishikawa, K.,Fujiyoshi, Y. (deposition date: 2026-04-06, release date: 2026-05-20, Last modification date: 2026-06-03)

Primary citation

Suzuki, S.,Tanaka, K.,Nishikawa, K.,Fujiyoshi, Y.
Cryo-EM Structure of the Human Mas Receptor Reveals N-terminal Occlusion of the Orthosteric Ligand Binding Pocket.
J.Mol.Biol., 438:169844-169844, 2026

PubMed Abstract: The Mas receptor (MasR) is a class A G protein-coupled receptor (GPCR) that mediates the counter-regulatory arm of the renin-angiotensin system through the ACE2-angiotensin-(1-7)-MasR axis and represents a promising therapeutic target for cardiovascular and metabolic disease. Despite its physiological importance, the structural basis of MasR has remained unknown. Here we report cryo-EM structures of human MasR in complex with heterotrimeric Gq at resolutions of 2.9 Å and 3.1 Å, determined for the full-length receptor and an N-terminally truncated variant (del2-25), respectively. These structures reveal that the receptor's own N-terminal peptide (residues 2-11) threads into and occludes the orthosteric binding pocket, functioning as an endogenous pseudo ligand. Functional mutagenesis and molecular dynamics simulations demonstrate that this N-terminal cap stably occupies the pocket but is dispensable for constitutive Gq coupling, distinguishing MasR from other N-terminal cap-forming GPCRs. Structural comparison with Mrgpr family members reveals a conserved Gq-coupling interface at the cytoplasmic face alongside divergent extracellular pocket architectures and identifies Y252 as a structural element that occludes a conserved sub-pocket present in Mrgpr paralogs. Molecular docking simulation of the MasR agonist AR234960 provides a structural template for orthosteric ligand design. Together, these findings establish the structural framework for MasR.

PubMed: 42105974
DOI: 10.1016/j.jmb.2026.169844

Experimental method

ELECTRON MICROSCOPY (3.2 Å)