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

Cryo-electron microscopy reveals the structure and activation mechanism of MrgD, a member of the Mas-related G protein-coupled receptor family of GPCRs involved in itch and nociception. 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 beta-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 beta-alanine-bound and apo states at 3.1 A and 2.8 A resolution, respectively. These structures show that beta-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.

Automated summary

Cryo-electron microscopy reveals the structure and activation mechanism of the MrgD receptor, providing insights into its ligand-dependent or constitutive activation.