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
  • 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.

Products