2. Academic Validation
  3. Structure, function and pharmacology of human itch GPCRs

Structure, function and pharmacology of human itch GPCRs

  • Nature. 2021 Dec;600(7887):170-175. doi: 10.1038/s41586-021-04126-6.
Can Cao # 1,  Hye Jin Kang # 1,  Isha Singh 2,  He Chen 3,  Chengwei Zhang 3,  Wenlei Ye 4,  Byron W Hayes 5,  Jing Liu 3,  Ryan H Gumpper 1,  Brian J Bender 2,  Samuel T Slocum 1,  Brian E Krumm 1,  Katherine Lansu 1,  John D McCorvy 1 6,  Wesley K Kroeze 1,  Justin G English 1 7,  Jeffrey F DiBerto 1,  Reid H J Olsen 1,  Xi-Ping Huang 1,  Shicheng Zhang 1,  Yongfeng Liu 1,  Kuglae Kim 1,  Joel Karpiak 2,  Lily Y Jan 4 8,  Soman N Abraham 5 9,  Jian Jin 3,  Brian K Shoichet 10,  Jonathan F Fay 11,  Bryan L Roth 12
Affiliations

Affiliations

  • 1 Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • 2 Department of Pharmaceutical Sciences, University of California San Francisco, School of Medicine, San Francisco, CA, USA.
  • 3 Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 4 Department of Physiology, University of California, San Francisco, San Francisco, CA, USA.
  • 5 Department of Pathology, Duke University Medical Center, Durham, NC, USA.
  • 6 Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.
  • 7 Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA.
  • 8 Howard Hughes Medical Institute, San Francisco, CA, USA.
  • 9 Program in Emerging Infectious Diseases, Duke-National University of Singapore, Singapore, Singapore.
  • 10 Department of Pharmaceutical Sciences, University of California San Francisco, School of Medicine, San Francisco, CA, USA. [email protected].
  • 11 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. [email protected].
  • 12 Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. [email protected].
  • # Contributed equally.
PMID: 34789874 DOI: 10.1038/s41586-021-04126-6
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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