Ligand recognition and G protein coupling of the human itch receptor MRGPRX1.

ABSTRACT: MRGPRX1, a Mas-related GPCR (MRGPR), is a key receptor for itch perception and targeting MRGPRX1 may have potential to treat both chronic itch and pain. Here we report cryo-EM structures of the MRGPRX1-Gi1 and MRGPRX1-Gq trimers in complex with two peptide ligands, BAM8-22 and CNF-Tx2. These structures reveal a shallow orthosteric pocket and its conformational plasticity for sensing multiple different peptidic itch allergens. Distinct from MRGPRX2, MRGPRX1 contains a unique pocket feature at the extracellular ends of TM3 and TM4 to accommodate the peptide C-terminal "RF/RY" motif, which could serve as key mechanisms for peptidic allergen recognition. Below the ligand binding pocket, the G^6.48XP^6.50F^6.51G^6.52X₍₂₎F/W^6.55 motif

SUBMITTER: Guo L 

PROVIDER: S-EPMC10435460 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature