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Title | Ligand recognition and allosteric modulation of the human MRGPRX1 receptor. |
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Journal, issue, pages | Nat Chem Biol, Vol. 19, Issue 4, Page 416-422, Year 2023 |
Publish date | Oct 27, 2022 |
Authors | Yongfeng Liu / Can Cao / Xi-Ping Huang / Ryan H Gumpper / Moira M Rachman / Sheng-Luen Shih / Brian E Krumm / Shicheng Zhang / Brian K Shoichet / Jonathan F Fay / Bryan L Roth / |
PubMed Abstract | The human MAS-related G protein-coupled receptor X1 (MRGPRX1) is preferentially expressed in the small-diameter primary sensory neurons and involved in the mediation of nociception and pruritus. ...The human MAS-related G protein-coupled receptor X1 (MRGPRX1) is preferentially expressed in the small-diameter primary sensory neurons and involved in the mediation of nociception and pruritus. Central activation of MRGPRX1 by the endogenous opioid peptide fragment BAM8-22 and its positive allosteric modulator ML382 has been shown to effectively inhibit persistent pain, making MRGPRX1 a promising target for non-opioid pain treatment. However, the activation mechanism of MRGPRX1 is still largely unknown. Here we report three high-resolution cryogenic electron microscopy structures of MRGPRX1-Gαq in complex with BAM8-22 alone, with BAM8-22 and ML382 simultaneously as well as with a synthetic agonist compound-16. These structures reveal the agonist binding mode for MRGPRX1 and illuminate the structural requirements for positive allosteric modulation. Collectively, our findings provide a molecular understanding of the activation and allosteric modulation of the MRGPRX1 receptor, which could facilitate the structure-based design of non-opioid pain-relieving drugs. |
External links | Nat Chem Biol / PubMed:36302898 |
Methods | EM (single particle) |
Resolution | 2.71 - 3.25 Å |
Structure data | EMDB-27752, PDB-8dwc: EMDB-27753, PDB-8dwg: EMDB-27754, PDB-8dwh: |
Chemicals | ChemComp-U39: ChemComp-U2U: |
Source |
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Keywords | SIGNALING PROTEIN / GPCR |