Structure, Function and Pharmacology of Human Itch GPCRs

Overview

Journal Nature

Specialty Science

Date 2021 Nov 18

PMID 34789874

Citations 72

Authors

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

Affiliations

Soon will be listed here.

Abstract

The MRGPRX family of receptors (MRGPRX1-4) is a family of mas-related G-protein-coupled receptors that have evolved relatively recently. Of these, MRGPRX2 and MRGPRX4 are key physiological and pathological mediators of itch and related mast cell-mediated hypersensitivity reactions. MRGPRX2 couples to both G and G in mast cells. Here we describe agonist-stabilized structures of MRGPRX2 coupled to G and G 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. Together, these findings should accelerate the structure-guided discovery of therapeutic agents for pain, itch and mast cell-mediated hypersensitivity.

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