Mas-related G-protein coupled receptor member X2
G protein-coupled receptor activity
Structure, function and pharmacology of human itch GPCRs.
The MRGPRX family of receptors (MRGPRX1-4) is a family of mas-related G-protein-coupled receptors that have evolved relatively recently<sup>1</sup>. Of these, MRGPRX2 and MRGPRX4 are key physiological and pathological mediators of itch and related mast cell-mediated hypersensitivity reactions<sup>2-5</sup>. MRGPRX2 couples to both G<sub>i</sub> and G<sub>q</sub> in mast cells<sup>6</sup>. Here we describe agonist-stabilized structures of MRGPRX2 coupled to G<sub>i1</sub> and G<sub>q</sub> 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<sub>q</sub>. Together, these findings should accelerate the structure-guided discovery of therapeutic agents for pain, itch and mast cell-mediated hypersensitivity.