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| Title | Cryo-EM Structure of the Human Mas Receptor Reveals N-terminal Occlusion of the Orthosteric Ligand Binding Pocket. |
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| Journal, issue, pages | J Mol Biol, Vol. 438, Issue 16, Page 169844, Year 2026 |
| Publish date | Aug 15, 2026 |
 Authors | Shota Suzuki / Kotaro Tanaka / Kouki Nishikawa / Yoshinori Fujiyoshi /  |
| 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 ...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. |
 External links | J Mol Biol / PubMed:42105974 |
| Methods | EM (single particle) |
| Resolution | 3.0 - 3.2 Å |
| Structure data | EMDB-80137, PDB-25ik: EMDB-80138, PDB-25il: |
| Source |
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 Keywords | MEMBRANE PROTEIN / GPCR / SIGNALING PROTEIN |
homo sapiens (human)
mus musculus (house mouse)
escherichia coli (E. coli)