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- EMDB-64830: Local refine map of HEP-50768-bound MRGPRX4 -

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Basic information

Entry
Database: EMDB / ID: EMD-64830
TitleLocal refine map of HEP-50768-bound MRGPRX4
Map dataLocal refinement map of MRGPRX4
Sample
  • Complex: Structure of an antagonist-bound MRGPRX4-Gq complex
    • Protein or peptide: Soluble cytochrome b562,Mas-related G-protein coupled receptor member X4
  • Ligand: 5-[2-fluoranyl-3-[(2S)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]phenyl]-1H-1,2,3,4-tetrazole
KeywordsG protein-coupled receptor / SIGNALING PROTEIN
Function / homology
Function and homology information


G protein-coupled bile acid receptor activity / sensory perception of itch / electron transport chain / G protein-coupled receptor activity / phospholipase C-activating G protein-coupled receptor signaling pathway / periplasmic space / electron transfer activity / iron ion binding / G protein-coupled receptor signaling pathway / heme binding / plasma membrane
Similarity search - Function
Mas-related G protein-coupled receptor family / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile.
Similarity search - Domain/homology
Soluble cytochrome b562 / Mas-related G-protein coupled receptor member X4
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.56 Å
AuthorsWang C / Zhang M / Cao C
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)GG9100007022 China
CitationJournal: Nat Chem Biol / Year: 2026
Title: Development of a clinically viable MRGPRX4 inverse agonist for cholestatic itch treatment.
Authors: Jun Yang / Ruichao Shen / Chunyu Wang / Wenneng Zhu / Han Ke / Junping Fan / Mengna Zhang / Yingjun Liu / Shuai Li / Guochuan Li / Xiaoming Wang / Yulong Li / Can Cao / Xiaoguang Lei /
Abstract: Chronic itch, particularly in cholestatic and uremic conditions, poses a notable clinical burden, yet treatment options remain inadequate. MRGPRX4 (hX4), a bile-acid-sensing G-protein-coupled ...Chronic itch, particularly in cholestatic and uremic conditions, poses a notable clinical burden, yet treatment options remain inadequate. MRGPRX4 (hX4), a bile-acid-sensing G-protein-coupled receptor predominantly expressed in human sensory neurons, has emerged as a critical mediator of cholestatic pruritus. Here we identified and characterized HEP-50768, a potent and selective small-molecule inverse agonist of hX4 through high-throughput screening and structure-activity optimization. Structural elucidation through cryo-electron microscopy of the hX4-inverse agonist complex structure revealed the unique binding mode and inhibitory mechanism of HEP-50768. In hX4-humanized rats, HEP-50768 robustly suppressed bile-acid-induced pruritic behaviors. Comprehensive preclinical absorption, distribution, metabolism, excretion and safety profiling was performed in both rats and monkeys, and these findings establish HEP-50768 as a promising therapeutic candidate for chronic itch, supporting its advancement to clinical evaluation.
History
DepositionMay 29, 2025-
Header (metadata) releaseMay 6, 2026-
Map releaseMay 6, 2026-
UpdateMay 6, 2026-
Current statusMay 6, 2026Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_64830.png

Downloads & links

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Map

FileDownload / File: emd_64830.map.gz / Format: CCP4 / Size: 166.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationLocal refinement map of MRGPRX4
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 352 pix.
= 288.64 Å		0.82 Å/pix.
x 352 pix.
= 288.64 Å		0.82 Å/pix.
x 352 pix.
= 288.64 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.82 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.7443362 - 1.00956
Average (Standard dev.)-0.000016559909 (±0.010741906)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions352352352
Spacing352352352
CellA=B=C: 288.63998 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_64830_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_64830_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Structure of an antagonist-bound MRGPRX4-Gq complex

EntireName: Structure of an antagonist-bound MRGPRX4-Gq complex
Components
  • Complex: Structure of an antagonist-bound MRGPRX4-Gq complex
    • Protein or peptide: Soluble cytochrome b562,Mas-related G-protein coupled receptor member X4
  • Ligand: 5-[2-fluoranyl-3-[(2S)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]phenyl]-1H-1,2,3,4-tetrazole

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Supramolecule #1: Structure of an antagonist-bound MRGPRX4-Gq complex

SupramoleculeName: Structure of an antagonist-bound MRGPRX4-Gq complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 150 KDa

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Macromolecule #1: Soluble cytochrome b562,Mas-related G-protein coupled receptor me...

MacromoleculeName: Soluble cytochrome b562,Mas-related G-protein coupled receptor member X4
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 53.39602 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DYKDDDDAKL QTMHHHHHHH HHHENLYFQG GTTMADLEDN WETLNDNLKV IEKADNAAQV KDALTKMRAA ALDAQKATPP KLEDKSPDS PEMKDFRHGF DILVGQIDDA LKLANEGKVK EAQAAAEQLK TTRNAYIQKY LGSTLEVLFQ GPDPTVPVFG T KLTPINGR ...String:
DYKDDDDAKL QTMHHHHHHH HHHENLYFQG GTTMADLEDN WETLNDNLKV IEKADNAAQV KDALTKMRAA ALDAQKATPP KLEDKSPDS PEMKDFRHGF DILVGQIDDA LKLANEGKVK EAQAAAEQLK TTRNAYIQKY LGSTLEVLFQ GPDPTVPVFG T KLTPINGR EETPCYNQTL SFTVLTCIIS LVGLTGNAVV LWLLGYRMRR NAVSIYILNL AAADFLFLSF QIIRSPLRLI NI SHLIRKI LVSVMTFPYF TGLSMLSAIS TERCLSVLWP IWYRCRRPTH LSAVVCVLLW GLSLLFSMLE WRFCDFLFSG ADS SWCETS DFIPVAWLIF LCVVLCVSSL VLLVRILCGS RKMPLTRLYV TILLTVLVFL LCGLPFGILG ALIYRMHLNL EVLY CHVYL VCMSLSSLNS SANPIIYFFV GSFRQRQNRQ NLKLVLQRAL QDKPEVDKGE GQLPEESLEL SGSRLGP

UniProtKB: Soluble cytochrome b562, Mas-related G-protein coupled receptor member X4

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Macromolecule #2: 5-[2-fluoranyl-3-[(2S)-5-(trifluoromethyl)-2,3-dihydro-1-benzofur...

MacromoleculeName: 5-[2-fluoranyl-3-[(2S)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]phenyl]-1H-1,2,3,4-tetrazole
type: ligand / ID: 2 / Number of copies: 1 / Formula: A1L9Y
Molecular weightTheoretical: 350.27 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1.5 mg/mL
BufferpH: 7.4
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 18.0 µm / Nominal defocus min: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1712286
CTF correctionType: NONE
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

8yrg

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.56 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. v4.41) / Number images used: 244199
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. v4.4.1)
FSC plot (resolution estimation)

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