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Ligand recognition and G protein coupling of the human itch receptor MRGPRX1

Lulu Guo1,2, Yumu Zhang3,4, Guoxing Fang5

  • 1Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China.

Nature Communications
|August 17, 2023
PubMed

Insights

Structural insights into Mas-related GPCR X1 (MRGPRX1) reveal how it detects itch-inducing peptides. This understanding is key for developing new treatments for chronic itch and pain by targeting MRGPRX1.

Area of Science:

  • Structural Biology
  • Neuroscience
  • Pharmacology

Background:

  • Mas-related GPCR X1 (MRGPRX1) is a critical receptor involved in itch perception.
  • Targeting MRGPRX1 offers potential therapeutic strategies for chronic itch and pain conditions.

Purpose of the Study:

  • To elucidate the structural mechanisms of MRGPRX1 activation by peptide ligands.
  • To understand the structural basis for MRGPRX1's interaction with Gi and Gq signaling proteins.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was used to determine the structures of MRGPRX1 in complex with Gi1 and Gq trimers.
  • Analysis of the orthosteric pocket, unique structural features, and G protein coupling interfaces.

Main Results:

  • Revealed a shallow, conformationally plastic orthosteric pocket for sensing diverse peptide allergens.
  • Identified a unique pocket feature accommodating the C-terminal "RF/RY" motif of peptides.
  • Discovered the essential G6.48XP6.50F6.51G6.52X(2)F/W6.55 motif for TM6 tilting and receptor activation.
  • Characterized structural elements crucial for both Gi and Gq signaling.

Conclusions:

  • The study provides high-resolution structures of MRGPRX1-Gi1 and MRGPRX1-Gq complexes.
  • These findings offer critical insights into MRGPRX1's recognition of peptidic allergens and its activation mechanisms.
  • The structural data advances our understanding of itch sensation and G protein signaling pathways, paving the way for targeted therapeutics.

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