8DWH

CryoEM structure of Gq-coupled MRGPRX1 with ligand Compound-16

Summary for 8DWH

• Entry DOI: 10.2210/pdb8dwh/pdb
• EMDB information: 27754
• Descriptor: Gs-mini-Gq chimera, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (5 entities in total)
• Functional Keywords: gpcr, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 110409.50

Authors

Liu, Y.,Cao, C.,Fay, J.F.,Roth, B.L. (deposition date: 2022-08-01, release date: 2022-11-02, Last modification date: 2024-10-30)

Primary citation

Liu, Y.,Cao, C.,Huang, X.P.,Gumpper, R.H.,Rachman, M.M.,Shih, S.L.,Krumm, B.E.,Zhang, S.,Shoichet, B.K.,Fay, J.F.,Roth, B.L.
Ligand recognition and allosteric modulation of the human MRGPRX1 receptor.
Nat.Chem.Biol., 19:416-422, 2023

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. 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.

PubMed: 36302898
DOI: 10.1038/s41589-022-01173-6

Experimental method

ELECTRON MICROSCOPY (3.25 Å)