Related Experiment Video

Updated: Jul 26, 2025

Cheek Injection Model for Simultaneous Measurement of Pain and Itch-related Behaviors
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Cheek Injection Model for Simultaneous Measurement of Pain and Itch-related Behaviors

Published on: September 27, 2019

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Mechanism of agonist-induced activation of the human itch receptor MRGPRX1

Bing Gan1,2, Leiye Yu1, Haifeng Yang3,4

  • 1Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China.

Plos Biology
|June 22, 2023
PubMed

Insights

Researchers determined the cryo-EM structure of Mas-related G-protein-coupled receptor X1 (MRGPRX1) in an active state. This provides insights into developing new therapeutics for itch and pain relief targeting MRGPRX1.

Area of Science:

  • Neuroscience
  • Structural Biology
  • Pharmacology

Background:

  • Mas-related G-protein-coupled receptors X1-X4 (MRGPRX1-X4) are primate-specific receptors involved in itch, pain, and inflammation.
  • MRGPRX1, expressed in sensory neurons, is a key target for managing itch and pain due to its dual signaling roles.

Purpose of the Study:

  • To determine the cryo-electron microscopy (cryo-EM) structure of the Gq-coupled MRGPRX1 in complex with a synthetic agonist.
  • To elucidate the structural basis for MRGPRX1 activation and agonist recognition.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was employed to resolve the structure of MRGPRX1 bound to compound 16.
  • A NanoBiT tethering strategy was utilized to facilitate complex formation and structural determination.
  • Receptor activation and itch behavior assays were conducted.

Main Results:

  • The cryo-EM structure of Gq-coupled MRGPRX1 in an active conformation was determined at 3.0 Å resolution.
  • Compound 16, a potent and selective agonist, was identified and complexed with MRGPRX1.
  • MRGPRX1 shares activation mechanisms with other MRGPRs, but possesses unique features in its orthosteric pocket for agonist binding.

Conclusions:

  • The study provides the first structural snapshot of MRGPRX1 in an active state, bound to a selective agonist.
  • Understanding the unique agonist recognition pattern of MRGPRX1 can guide the design of specific modulators.
  • These findings offer a structural basis for developing novel therapeutics for itch relief and analgesia targeting MRGPRX1.

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