Structure, function and pharmacology of human itch GPCRs

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 ZhangYongfeng Liu, Kuglae Kim, Joel Karpiak, Lily Y. Jan, Soman N. Abraham, Jian Jin, Brian K. Shoichet, Jonathan F. Fay, Bryan L. Roth

Research output: Contribution to journalArticlepeer-review

68 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)170-175
Number of pages6
Issue number7887
Publication statusPublished - 2021 Dec 2

Bibliographical note

Funding Information:
Acknowledgements This work was supported by NIH grants U24DA116195 (to B.L.R., B.K.S. and J.J.) and R35GM122481 (to B.K.S.), and by the Michael Hooker Distinguished Professorship to B.L.R. and NIH grant R01-DK121969, R01-DK121032 and R56-AI139620 to S.N.A. We thank J. Peck and J. Strauss of the UNC Cryo-EM Core Facility for technical assistance in this project. W.Y. is partly supported by Program for Breakthrough Biomedical Research funded by the Sandler Foundation, University of California, San Francisco. L.Y.J. is a Howard Hughes Medical Institute investigator. We thank S.-L. Shyng for the plasmids encoding human Kir6.2 and SUR1. The Titan X Pascal used for this research was kindly donated to J.F.F. by the NVIDIA Corporation.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.

All Science Journal Classification (ASJC) codes

  • General


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