Faculty Collaboration Database

Structure, function and pharmacology of human itch GPCRs. Nature 2021 Dec;600(7887):170-175

Date

11/19/2021

Pubmed ID

34789874

Pubmed Central ID

PMC9150435

DOI

10.1038/s41586-021-04126-6

Scopus ID

2-s2.0-85119397373 (requires institutional sign-in at Scopus site)   183 Citations

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.

Author List

Cao C, Kang HJ, Singh I, Chen H, Zhang C, Ye W, Hayes BW, Liu J, Gumpper RH, Bender BJ, Slocum ST, Krumm BE, Lansu K, McCorvy JD, Kroeze WK, English JG, DiBerto JF, Olsen RHJ, Huang XP, Zhang S, Liu Y, Kim K, Karpiak J, Jan LY, Abraham SN, Jin J, Shoichet BK, Fay JF, Roth BL

Authors

Byron W. Hayes Postdoctoral Researcher in the Physiology department at Medical College of Wisconsin
John McCorvy PhD Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Cryoelectron Microscopy
Drug Inverse Agonism
GTP-Binding Protein alpha Subunits, Gi-Go
GTP-Binding Protein alpha Subunits, Gq-G11
Humans
Models, Molecular
Nerve Tissue Proteins
Pruritus
Receptors, G-Protein-Coupled
Receptors, Neuropeptide