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Papers of the Week

2022 Jul 15

Commun Biol



Structural insight into the activation mechanism of MrgD with heterotrimeric Gi-protein revealed by cryo-EM.


Suzuki S, Iida M, Hiroaki Y, Tanaka K, Kawamoto A, Kato T, Oshima A
Commun Biol. 2022 Jul 15; 5(1):707.
PMID: 35840655.


MrgD, a member of the Mas-related G protein-coupled receptor (MRGPR) family, has high basal activity for Gi activation. It recognizes endogenous ligands, such as β-alanine, and is involved in pain and itch signaling. The lack of a high-resolution structure for MrgD hinders our understanding of whether its activation is ligand-dependent or constitutive. Here, we report two cryo-EM structures of the MrgD-Gi complex in the β-alanine-bound and apo states at 3.1 Å and 2.8 Å resolution, respectively. These structures show that β-alanine is bound to a shallow pocket at the extracellular domains. The extracellular half of the sixth transmembrane helix undergoes a significant movement and is tightly packed into the third transmembrane helix through hydrophobic residues, creating the active form. Our structures demonstrate a structural basis for the characteristic ligand recognition of MrgD. These findings provide a framework to guide drug designs targeting the MrgD receptor.