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 recently1. Of these, MRGPRX2 and MRGPRX4 are key physiological and pathological mediators of itch and related mast cell-mediated hypersensitivity reactions2-5. MRGPRX2 couples to both Gi and Gq in mast cells6. Here we describe agonist-stabilized structures of MRGPRX2 coupled to Gi1 and Gq 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 Gq. Together, these findings should accelerate the structure-guided discovery of therapeutic agents for pain, itch and mast cell-mediated hypersensitivity.
Cao, C; Kang, HJ; Singh, I; Chen, H; Zhang, C; Ye, W; Hayes, BW; Liu, J; Gumpper, RH; Bender, BJ; Slocum, ST; Krumm, BE; Lansu, K; McCorvy, JD; Kroeze, WK; English, JG; DiBerto, JF; Olsen, RHJ; Huang, X-P; Zhang, S; Liu, Y; Kim, K; Karpiak, J; Jan, LY; Abraham, SN; Jin, J; Shoichet, BK; Fay, JF; Roth, BL
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