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Ligand recognition and allosteric modulation of the human MRGPRX1 receptor.
- Source :
-
Nature chemical biology [Nat Chem Biol] 2023 Apr; Vol. 19 (4), pp. 416-422. Date of Electronic Publication: 2022 Oct 27. - Publication Year :
- 2023
-
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. 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.<br /> (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Details
- Language :
- English
- ISSN :
- 1552-4469
- Volume :
- 19
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Nature chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 36302898
- Full Text :
- https://doi.org/10.1038/s41589-022-01173-6