Structure, function and pharmacology of human itch GPCRs
- Cao, Can;
- Kang, Hye Jin;
- Singh, Isha;
- Chen, He;
- Zhang, Chengwei;
- Ye, Wenlei;
- Hayes, Byron W;
- Liu, Jing;
- Gumpper, Ryan H;
- Bender, Brian J;
- Slocum, Samuel T;
- Krumm, Brian E;
- Lansu, Katherine;
- McCorvy, John D;
- Kroeze, Wesley K;
- English, Justin G;
- DiBerto, Jeffrey F;
- Olsen, Reid HJ;
- Huang, Xi-Ping;
- Zhang, Shicheng;
- Liu, Yongfeng;
- Kim, Kuglae;
- Karpiak, Joel;
- Jan, Lily Y;
- Abraham, Soman N;
- Jin, Jian;
- Shoichet, Brian K;
- Fay, Jonathan F;
- Roth, Bryan L
- et al.
Published Web Location
https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/34789874/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.
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