7vuz Citations

Structure, function and pharmacology of human itch receptor complexes.

Nature 600 164-169 (2021)
Related entries: 7vdh, 7vdl, 7vdm, 7vuy, 7vv0, 7vv3, 7vv4, 7vv5, 7vv6

Cited: 44 times
EuropePMC logo PMID: 34789875

Abstract

In the clades of animals that diverged from the bony fish, a group of Mas-related G-protein-coupled receptors (MRGPRs) evolved that have an active role in itch and allergic signals1,2. As an MRGPR, MRGPRX2 is known to sense basic secretagogues (agents that promote secretion) and is involved in itch signals and eliciting pseudoallergic reactions3-6. MRGPRX2 has been targeted by drug development efforts to prevent the side effects induced by certain drugs or to treat allergic diseases. Here we report a set of cryo-electron microscopy structures of the MRGPRX2-Gi1 trimer in complex with polycationic compound 48/80 or with inflammatory peptides. The structures of the MRGPRX2-Gi1 complex exhibited shallow, solvent-exposed ligand-binding pockets. We identified key common structural features of MRGPRX2 and describe a consensus motif for peptidic allergens. Beneath the ligand-binding pocket, the unusual kink formation at transmembrane domain 6 (TM6) and the replacement of the general toggle switch from Trp6.48 to Gly6.48 (superscript annotations as per Ballesteros-Weinstein nomenclature) suggest a distinct activation process. We characterized the interfaces of MRGPRX2 and the Gi trimer, and mapped the residues associated with key single-nucleotide polymorphisms on both the ligand and G-protein interfaces of MRGPRX2. Collectively, our results provide a structural basis for the sensing of cationic allergens by MRGPRX2, potentially facilitating the rational design of therapies to prevent unwanted pseudoallergic reactions.

Reviews - 7vuz mentioned but not cited (1)

  1. G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders. Wong TS, Li G, Li S, Gao W, Chen G, Gan S, Zhang M, Li H, Wu S, Du Y. Signal Transduct Target Ther 8 177 (2023)


Reviews citing this publication (9)

  1. Specialized Pro-Resolving Mediators as Resolution Pharmacology for the Control of Pain and Itch. Ji RR. Annu Rev Pharmacol Toxicol 63 273-293 (2023)
  2. Allergy, Anaphylaxis, and Nonallergic Hypersensitivity: IgE, Mast Cells, and Beyond. Vitte J, Vibhushan S, Bratti M, Montero-Hernandez JE, Blank U. Med Princ Pract 31 501-515 (2022)
  3. The translational revolution of itch. Kim BS. Neuron 110 2209-2214 (2022)
  4. Molecular basis of opioid receptor signaling. Che T, Roth BL. Cell 186 5203-5219 (2023)
  5. The structure, function, and pharmacology of MRGPRs. Cao C, Roth BL. Trends Pharmacol Sci 44 237-251 (2023)
  6. Inflammation and Organ Injury the Role of Substance P and Its Receptors. Zhu Z, Bhatia M. Int J Mol Sci 24 6140 (2023)
  7. Allosteric modulation of G protein-coupled receptors as a novel therapeutic strategy in neuropathic pain. Zhu C, Lan X, Wei Z, Yu J, Zhang J. Acta Pharm Sin B 14 67-86 (2024)
  8. The MRGPR family of receptors in immunity. Gour N, Dong X. Immunity 57 28-39 (2024)
  9. G protein-coupled receptors as targets for transformative neuropsychiatric therapeutics. Schmitz GP, Roth BL. Am J Physiol Cell Physiol 325 C17-C28 (2023)

Articles citing this publication (34)