Structure, function and pharmacology of human itch GPCRs

Structural studies of the itch receptors MRGPRX2 and MRGPRX4 in complex with endogenous and synthetic ligands provide a basis for the development of therapeutic compounds for pain, itch and mast cell-mediated hypersensitivity. The MRGPRX family of receptors (MRGPRX1-4) is a family of mas-related G-protein-coupled receptors that have evolved relatively recently(1). Of these, MRGPRX2 and MRGPRX4 are key physiological and pathological mediators of itch and related mast cell-mediated hypersensitivity reactions(2-5). MRGPRX2 couples to both G(i) and G(q) in mast cells(6). Here we describe agonist-stabilized structures of MRGPRX2 coupled to G(i1) and G(q) in ternary complexes with the endogenous peptide cortistatin-14 and with a synthetic agonist probe, respectively, and the development of potent antagonist probes for MRGPRX2. We also describe a specific MRGPRX4 agonist and the structure of this agonist in a complex with MRGPRX4 and G(q). Together, these findings should accelerate the structure-guided discovery of therapeutic agents for pain, itch and mast cell-mediated hypersensitivity.

Automated summary

Structural studies of MRGPRX2 and MRGPRX4 in complex with endogenous and synthetic ligands provide insights for developing therapeutic compounds for pain, itch, and mast cell-mediated hypersensitivity. These receptors are key mediators of itch and related mast cell-mediated hypersensitivity reactions.