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; Bryan L Roth

doi:10.1038/s41586-021-04126-6

Structure, function and pharmacology of human itch GPCRs

Nature. 2021 Dec;600(7887):170-175. doi: 10.1038/s41586-021-04126-6. Epub 2021 Nov 17.

Authors

Can Cao^#¹, Hye Jin Kang^#¹, Isha Singh², He Chen³, Chengwei Zhang³, Wenlei Ye⁴, Byron W Hayes⁵, Jing Liu³, Ryan H Gumpper¹, Brian J Bender², Samuel T Slocum¹, Brian E Krumm¹, Katherine Lansu¹, John D McCorvy^{1

6}, Wesley K Kroeze¹, Justin G English^{1

7}, Jeffrey F DiBerto¹, Reid H J Olsen¹, Xi-Ping Huang¹, Shicheng Zhang¹, Yongfeng Liu¹, Kuglae Kim¹, Joel Karpiak², Lily Y Jan^{4

8}, Soman N Abraham^{5

9}, Jian Jin³, Brian K Shoichet¹⁰, Jonathan F Fay¹¹, Bryan L Roth¹²

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. bshoichet@gmail.com.
¹¹ Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. fayj@unc.edu.
¹² Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. bryan_roth@med.unc.edu.

^# Contributed equally.

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 reactions^2-5. MRGPRX2 couples to both G_i and G_q in mast cells⁶. Here we describe agonist-stabilized structures of MRGPRX2 coupled to G_i1 and G_q 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 G_q. Together, these findings should accelerate the structure-guided discovery of therapeutic agents for pain, itch and mast cell-mediated hypersensitivity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cryoelectron Microscopy*
Drug Inverse Agonism
GTP-Binding Protein alpha Subunits, Gi-Go / chemistry
GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
GTP-Binding Protein alpha Subunits, Gi-Go / ultrastructure
GTP-Binding Protein alpha Subunits, Gq-G11 / chemistry
GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
GTP-Binding Protein alpha Subunits, Gq-G11 / ultrastructure
Humans
Models, Molecular
Nerve Tissue Proteins / antagonists & inhibitors*
Nerve Tissue Proteins / chemistry*
Nerve Tissue Proteins / metabolism
Nerve Tissue Proteins / ultrastructure
Pruritus / metabolism*
Receptors, G-Protein-Coupled / agonists*
Receptors, G-Protein-Coupled / antagonists & inhibitors*
Receptors, G-Protein-Coupled / chemistry*
Receptors, G-Protein-Coupled / metabolism
Receptors, G-Protein-Coupled / ultrastructure
Receptors, Neuropeptide / antagonists & inhibitors*
Receptors, Neuropeptide / chemistry*
Receptors, Neuropeptide / metabolism
Receptors, Neuropeptide / ultrastructure

Substances

MRGPRX2 protein, human
MRGPRX4 protein, human
Nerve Tissue Proteins
Receptors, G-Protein-Coupled
Receptors, Neuropeptide
GTP-Binding Protein alpha Subunits, Gi-Go
GTP-Binding Protein alpha Subunits, Gq-G11

Abstract

Publication types

MeSH terms

Substances

Grants and funding