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 Zhang, Yongfeng Liu, Kuglae Kim, Joel Karpiak, Lily Y. Jan, Soman N. Abraham, Jian Jin, Brian K. Shoichet (), Jonathan F. Fay () and Bryan L. Roth ()
Additional contact information
Can Cao: University of North Carolina at Chapel Hill School of Medicine
Hye Jin Kang: University of North Carolina at Chapel Hill School of Medicine
Isha Singh: University of California San Francisco, School of Medicine
He Chen: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
Chengwei Zhang: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
Wenlei Ye: University of California, San Francisco
Byron W. Hayes: Duke University Medical Center
Jing Liu: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
Ryan H. Gumpper: University of North Carolina at Chapel Hill School of Medicine
Brian J. Bender: University of California San Francisco, School of Medicine
Samuel T. Slocum: University of North Carolina at Chapel Hill School of Medicine
Brian E. Krumm: University of North Carolina at Chapel Hill School of Medicine
Katherine Lansu: University of North Carolina at Chapel Hill School of Medicine
John D. McCorvy: University of North Carolina at Chapel Hill School of Medicine
Wesley K. Kroeze: University of North Carolina at Chapel Hill School of Medicine
Justin G. English: University of North Carolina at Chapel Hill School of Medicine
Jeffrey F. DiBerto: University of North Carolina at Chapel Hill School of Medicine
Reid H. J. Olsen: University of North Carolina at Chapel Hill School of Medicine
Xi-Ping Huang: University of North Carolina at Chapel Hill School of Medicine
Shicheng Zhang: University of North Carolina at Chapel Hill School of Medicine
Yongfeng Liu: University of North Carolina at Chapel Hill School of Medicine
Kuglae Kim: University of North Carolina at Chapel Hill School of Medicine
Joel Karpiak: University of California San Francisco, School of Medicine
Lily Y. Jan: University of California, San Francisco
Soman N. Abraham: Duke University Medical Center
Jian Jin: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
Brian K. Shoichet: University of California San Francisco, School of Medicine
Jonathan F. Fay: University of North Carolina at Chapel Hill School of Medicine
Bryan L. Roth: University of North Carolina at Chapel Hill School of Medicine

Nature, 2021, vol. 600, issue 7887, 170-175

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-04126-6

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