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Structure, function and pharmacology of human itch GPCRs.

Nature (2021-11-19)
Can Cao, Hye Jin Kang, Isha Singh, He Chen, Chengwei Zhang, Wenlei Ye, Byron W Hayes, Jing Liu, Ryan H Gumpper, Brian J Bender, Samuel T Slocum, Brian E Krumm, Katherine Lansu, John D McCorvy, Wesley K Kroeze, Justin G English, Jeffrey F DiBerto, Reid H J Olsen, Xi-Ping Huang, Shicheng Zhang, Yongfeng Liu, Kuglae Kim, Joel Karpiak, Lily Y Jan, Soman N Abraham, Jian Jin, Brian K Shoichet, Jonathan F Fay, Bryan L Roth
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
MS47134, ≥98% (HPLC)
Sigma-Aldrich
X4-2, ≥98% (HPLC)
Sigma-Aldrich
Monoclonal ANTI-FLAG® M2-Peroxidase (HRP) antibody produced in mouse, clone M2, purified immunoglobulin, buffered aqueous glycerol solution