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- EMDB-68873: Cryo-EM structure of the MRGPRX4-miniGsq complex bound to the inv... -

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Entry
Database: EMDB / ID: EMD-68873
TitleCryo-EM structure of the MRGPRX4-miniGsq complex bound to the inverse agonist cmpd54-4
Map data
Sample
  • Complex: GPCR bound with a ligand
    • Protein or peptide: Gs-mini-Gq chimera
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: scFv16
    • Protein or peptide: Soluble cytochrome b562,Mas-related G-protein coupled receptor member X4
  • Ligand: (2~{S})-2-[[3-[[2-chloranyl-4-(trifluoromethyl)phenoxy]methyl]phenyl]carbonylamino]propanoic acid
KeywordsMEMBRANE 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 / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G protein-coupled acetylcholine receptor signaling pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors ...G protein-coupled bile acid receptor activity / sensory perception of itch / electron transport chain / G protein-coupled receptor activity / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G protein-coupled acetylcholine receptor signaling pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / ADP signalling through P2Y purinoceptor 1 / cellular response to catecholamine stimulus / G beta:gamma signalling through PI3Kgamma / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / heterotrimeric G-protein complex / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / cellular response to prostaglandin E stimulus / GPER1 signaling / G alpha (12/13) signalling events / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / extracellular vesicle / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / GTPase binding / Ca2+ pathway / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / electron transfer activity / Extra-nuclear estrogen signaling / periplasmic space / iron ion binding / G protein-coupled receptor signaling pathway / lysosomal membrane / heme binding / GTPase activity / synapse / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytosol
Similarity search - Function
Mas-related G protein-coupled receptor family / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs ...Mas-related G protein-coupled receptor family / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / Guanine nucleotide-binding protein, beta subunit / G protein beta WD-40 repeat protein / G-protein, beta subunit / 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. / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Soluble cytochrome b562 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Mas-related G protein-coupled receptor member X4
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.98 Å
AuthorsCao C / Wang C / Zhang M / Ji Z
Funding support China, 2 items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2025YFA1309100 China
National Natural Science Foundation of China (NSFC)82504820 China
CitationJournal: Cell Discov / Year: 2026
Title: Structural insights into the ligand modulation of MRGPRX4 conformational plasticity.
Authors: Mengna Zhang / Yongxia Wang / Yun Huang / Yaqi Liang / Pengxiao Chen / Zheng Ji / Minghu Song / He Chen / Chunyu Wang / Can Cao /
Abstract: Chronic pruritus is a debilitating condition with limited treatment options, particularly in cholestatic liver diseases, where bile acid dysregulation is a known trigger. Although Mas-related G ...Chronic pruritus is a debilitating condition with limited treatment options, particularly in cholestatic liver diseases, where bile acid dysregulation is a known trigger. Although Mas-related G protein-coupled receptor X4 (MRGPRX4) has recently been identified as a key mediator of bile acid-induced pruritus, the structural mechanisms underlying its inhibition remain poorly understood, hindering the development of therapeutic antagonists. Here, we report the cryo-electron microscopy structures of MRGPRX4 in three distinct states: agonist-bound state, antagonist-bound state, and apo state. Our structures reveal a previously unrecognized antagonist-binding site that is structurally distinct from those engaged by agonists. Complementary functional assays and molecular dynamics simulations further demonstrate that the extracellular pocket of MRGPRX4 undergoes pronounced ligand-dependent conformational rearrangements upon binding to both the agonist and the antagonist. Collectively, these findings elucidate the conformational plasticity underlying MRGPRX4 activity modulation and establish a structural framework for the rational design of MRGPRX4 antagonists that target chronic pruritus.
History
DepositionFeb 1, 2026-
Header (metadata) releaseOct 14, 2026-
Map releaseOct 14, 2026-
UpdateNov 4, 2026-
Current statusNov 4, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_68873.png

Downloads & links

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Map

FileDownload / File: emd_68873.map.gz / Format: CCP4 / Size: 172.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 356 pix.
= 291.92 Å		0.82 Å/pix.
x 356 pix.
= 291.92 Å		0.82 Å/pix.
x 356 pix.
= 291.92 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.82 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.4
Minimum - Maximum-3.3353722 - 5.0069036
Average (Standard dev.)-0.00048106597 (±0.06232959)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions356356356
Spacing356356356
CellA=B=C: 291.91998 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_68873_half_map_1.map
Projections & Slices
AxesZYX

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Density Histograms

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Half map: #2

Fileemd_68873_half_map_2.map
Projections & Slices
AxesZYX

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Histogram (log scale)

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Sample components

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Entire : GPCR bound with a ligand

EntireName: GPCR bound with a ligand
Components
  • Complex: GPCR bound with a ligand
    • Protein or peptide: Gs-mini-Gq chimera
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: scFv16
    • Protein or peptide: Soluble cytochrome b562,Mas-related G-protein coupled receptor member X4
  • Ligand: (2~{S})-2-[[3-[[2-chloranyl-4-(trifluoromethyl)phenoxy]methyl]phenyl]carbonylamino]propanoic acid

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Supramolecule #1: GPCR bound with a ligand

SupramoleculeName: GPCR bound with a ligand / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 157.19 KDa

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Macromolecule #1: Gs-mini-Gq chimera

MacromoleculeName: Gs-mini-Gq chimera / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 28.084832 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGSTVSAEDK AAAERSKMID KNLREDGEKA RRTLRLLLLG ADNSGKSTIV KQMRILHGGS GGSGGTSGIF ETKFQVDKVN FHMFDVGGQ RDERRKWIQC FNDVTAIIFV VDSSDYNRLQ EALNDFKSIW NNRWLRTISV ILFLNKQDLL AEKVLAGKSK I EDYFPEFA ...String:
MGSTVSAEDK AAAERSKMID KNLREDGEKA RRTLRLLLLG ADNSGKSTIV KQMRILHGGS GGSGGTSGIF ETKFQVDKVN FHMFDVGGQ RDERRKWIQC FNDVTAIIFV VDSSDYNRLQ EALNDFKSIW NNRWLRTISV ILFLNKQDLL AEKVLAGKSK I EDYFPEFA RYTTPEDATP EPGEDPRVTR AKYFIRKEFV DISTASGDGR HICYPHFTCA VDTENARRIF NDCKDIILQM NL REYNLV

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Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.418086 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MHHHHHHLEV LFQGPGSSGS ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLV SASQDGKLII WDSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG H TGYLSCCR ...String:
MHHHHHHLEV LFQGPGSSGS ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLV SASQDGKLII WDSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG H TGYLSCCR FLDDNQIVTS SGDTTCALWD IETGQQTTTF TGHTGDVMSL SLAPDTRLFV SGACDASAKL WDVREGMCRQ TF TGHESDI NAICFFPNGN AFATGSDDAT CRLFDLRADQ ELMTYSHDNI ICGITSVSFS KSGRLLLAGY DDFNCNVWDA LKA DRAGVL AGHDNRVSCL GVTDDGMAVA TGSWDSFLKI WN

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #4: scFv16

MacromoleculeName: scFv16 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 28.668922 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String:
DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL KAAALEVLFQ GPHHHHHHHH

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Macromolecule #5: 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: 5 / 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 #6: (2~{S})-2-[[3-[[2-chloranyl-4-(trifluoromethyl)phenoxy]methyl]phe...

MacromoleculeName: (2~{S})-2-[[3-[[2-chloranyl-4-(trifluoromethyl)phenoxy]methyl]phenyl]carbonylamino]propanoic acid
type: ligand / ID: 6 / Number of copies: 1 / Formula: A1E43
Molecular weightTheoretical: 401.764 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

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (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: 1.6 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

8yrg

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.98 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 432382
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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