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- PDB-9v82: Local refine map of HEP-50768-bound MRGPRX4 -

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Basic information

Entry
Database: PDB / ID: 9v82
TitleLocal refine map of HEP-50768-bound MRGPRX4
ComponentsSoluble cytochrome b562,Mas-related G-protein coupled receptor member X4
KeywordsSIGNALING PROTEIN / G protein-coupled receptor
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 speciesEscherichia coli (E. coli)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.56 Å
AuthorsWang, C. / Zhang, M. / Cao, C.
Funding support China, 1items
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, 2025Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 6, 2026Provider: repository / Type: Initial release
Revision 1.0May 6, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0May 6, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0May 6, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 6, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 6, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0May 6, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
R: Soluble cytochrome b562,Mas-related G-protein coupled receptor member X4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,7462
Polymers53,3961
Non-polymers3501
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Soluble cytochrome b562,Mas-related G-protein coupled receptor member X4 / Cytochrome b-562 / Sensory neuron-specific G-protein coupled receptor 5/6


Mass: 53396.020 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli (E. coli), (gene. exp.) Homo sapiens (human)
Gene: cybC, MRGPRX4, MRGX4, SNSR5, SNSR6 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P0ABE7, UniProt: Q96LA9
#2: Chemical ChemComp-A1L9Y / 5-[2-fluoranyl-3-[(2S)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]phenyl]-1H-1,2,3,4-tetrazole


Mass: 350.270 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H10F4N4O / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Structure of an antagonist-bound MRGPRX4-Gq complex / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.15 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm) / Cell: sf9
Buffer solutionpH: 7.4
SpecimenConc.: 1.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 18000 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCv4.4.1particle selection
11cryoSPARCv4.4.1final Euler assignment
13cryoSPARCv4.413D reconstruction
CTF correctionType: NONE
Particle selectionNum. of particles selected: 1712286
3D reconstructionResolution: 2.56 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 244199 / Symmetry type: POINT
RefinementCross valid method: NONE

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