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- EMDB-37191: CryoEM structure of Gq coupled MRGPRX4 with agonist DCA-3P, local -

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Basic information

Entry
Database: EMDB / ID: EMD-37191
TitleCryoEM structure of Gq coupled MRGPRX4 with agonist DCA-3P, local
Map data
Sample
  • Complex: Cryo-EM structure of MRGPRX4 complex with agonist DCA-3P
    • Protein or peptide: Soluble cytochrome b562,Mas-related G-protein coupled receptor member X4,Green fluorescent protein
  • Ligand: (4~{R})-4-[(3~{R},5~{R},8~{R},9~{S},10~{S},12~{S},13~{R},14~{S},17~{R})-10,13-dimethyl-12-oxidanyl-3-phosphonooxy-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1~{H}-cyclopenta[a]phenanthren-17-yl]pentanoic acid
KeywordsMRGPRX4 / Bile acid / Cholestatic itch / GPCR / Agonist / MEMBRANE PROTEIN
Function / homology
Function and homology information


bioluminescence / generation of precursor metabolites and energy / electron transport chain / G protein-coupled receptor activity / periplasmic space / electron transfer activity / G protein-coupled receptor signaling pathway / iron ion binding / heme binding / plasma membrane
Similarity search - Function
Mas-related G protein-coupled receptor family / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like ...Mas-related G protein-coupled receptor family / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family)
Similarity search - Domain/homology
Soluble cytochrome b562 / Green fluorescent protein / Mas-related G-protein coupled receptor member X4
Similarity search - Component
Biological speciesHomo sapiens (human) / Aequorea victoria (jellyfish)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsYang J / Fan JP / Lei XG
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Cell / Year: 2024
Title: Structure-guided discovery of bile acid derivatives for treating liver diseases without causing itch.
Authors: Jun Yang / Tianjun Zhao / Junping Fan / Huaibin Zou / Guangyi Lan / Fusheng Guo / Yaocheng Shi / Han Ke / Huasheng Yu / Zongwei Yue / Xin Wang / Yingjie Bai / Shuai Li / Yingjun Liu / ...Authors: Jun Yang / Tianjun Zhao / Junping Fan / Huaibin Zou / Guangyi Lan / Fusheng Guo / Yaocheng Shi / Han Ke / Huasheng Yu / Zongwei Yue / Xin Wang / Yingjie Bai / Shuai Li / Yingjun Liu / Xiaoming Wang / Yu Chen / Yulong Li / Xiaoguang Lei /
Abstract: Chronic itch is a debilitating symptom profoundly impacting the quality of life in patients with liver diseases like cholestasis. Activation of the human G-protein coupled receptor, MRGPRX4 (hX4), by ...Chronic itch is a debilitating symptom profoundly impacting the quality of life in patients with liver diseases like cholestasis. Activation of the human G-protein coupled receptor, MRGPRX4 (hX4), by bile acids (BAs) is implicated in promoting cholestasis itch. However, the detailed underlying mechanisms remain elusive. Here, we identified 3-sulfated BAs that are elevated in cholestatic patients with itch symptoms. We solved the cryo-EM structure of hX4-Gq in a complex with 3-phosphated deoxycholic acid (DCA-3P), a mimic of the endogenous 3-sulfated deoxycholic acid (DCA-3S). This structure revealed an unprecedented ligand-binding pocket in MRGPR family proteins, highlighting the crucial role of the 3-hydroxyl (3-OH) group on BAs in activating hX4. Guided by this structural information, we designed and developed compound 7 (C7), a BA derivative lacking the 3-OH. Notably, C7 effectively alleviates hepatic injury and fibrosis in liver disease models while significantly mitigating the itch side effects.
History
DepositionAug 14, 2023-
Header (metadata) releaseNov 6, 2024-
Map releaseNov 6, 2024-
UpdateDec 25, 2024-
Current statusDec 25, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_37191.png

Downloads & links

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Map

FileDownload / File: emd_37191.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.04 Å/pix.
x 256 pix.
= 266.24 Å		1.04 Å/pix.
x 256 pix.
= 266.24 Å		1.04 Å/pix.
x 256 pix.
= 266.24 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.04 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.52
Minimum - Maximum-1.5280142 - 4.984838
Average (Standard dev.)-0.0012007875 (±0.055416424)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 266.24 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_37191_half_map_1.map
Projections & Slices
AxesZYX

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Histogram

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Half map: #1

Fileemd_37191_half_map_2.map
Projections & Slices
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Sample components

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Entire : Cryo-EM structure of MRGPRX4 complex with agonist DCA-3P

EntireName: Cryo-EM structure of MRGPRX4 complex with agonist DCA-3P
Components
  • Complex: Cryo-EM structure of MRGPRX4 complex with agonist DCA-3P
    • Protein or peptide: Soluble cytochrome b562,Mas-related G-protein coupled receptor member X4,Green fluorescent protein
  • Ligand: (4~{R})-4-[(3~{R},5~{R},8~{R},9~{S},10~{S},12~{S},13~{R},14~{S},17~{R})-10,13-dimethyl-12-oxidanyl-3-phosphonooxy-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1~{H}-cyclopenta[a]phenanthren-17-yl]pentanoic acid

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Supramolecule #1: Cryo-EM structure of MRGPRX4 complex with agonist DCA-3P

SupramoleculeName: Cryo-EM structure of MRGPRX4 complex with agonist DCA-3P
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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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,Green fluorescent protein
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Aequorea victoria (jellyfish)
Molecular weightTheoretical: 79.79568 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DYKDDDDKEF ADLEDNWETL NDNLKVIEKA DNAAQVKDAL TKMRAAALDA QKATPPKLED KSPDSPEMKD FRHGFDILVG QIDDALKLA NEGKVKEAQA AAEQLKTTRN AYIQKYLMDP TVPVFGTKLT PINGREETPC YNQTLSFTVL TCIISLVGLT G NAVVLWLL ...String:
DYKDDDDKEF ADLEDNWETL NDNLKVIEKA DNAAQVKDAL TKMRAAALDA QKATPPKLED KSPDSPEMKD FRHGFDILVG QIDDALKLA NEGKVKEAQA AAEQLKTTRN AYIQKYLMDP TVPVFGTKLT PINGREETPC YNQTLSFTVL TCIISLVGLT G NAVVLWLL GYRMRRNAVS IYILNLAAAD FLFLSFQIIR LPLRLINISH LIRKILVSVM TFPYFTGLSM LSAISTERCL SV LWPIWYR CRRPTHLSAV VCVLLWGLSL LFSMLEWRFC DFLFSGADSS WCETSDFIPV AWLIFLCVVL CVSSLVLLVR ILC GSRKMP LTRLYVTILL TVLVFLLCGL PFGILGALIY RMHLNLEVLY CHVYLVCMSL SSLNSSANPI IYFFVGSFRQ RQNR QNLKL VLQRALQDKP EVDKGEGQLP EESLELSGSR LGPLELEVLF QGPSKGEELF TGVVPILVEL DGDVNGHKFS VRGEG EGDA TNGKLTLKFI CTTGKLPVPW PTLVTTLTYG VQCFSRYPDH MKRHDFFKSA MPEGYVQERT ISFKDDGTYK TRAEVK FEG DTLVNRIELK GIDFKEDGNI LGHKLEYNFN SHNVYITADK QKNGIKANFK IRHNVEDGSV QLADHYQQNT PIGDGPV LL PDNHYLSTQS VLSKDPNEKR DHMVLLEFVT AAGITHGMDE WSHPQFEKGG GSGGGSGGSA WSHPQFEK

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

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Macromolecule #2: (4~{R})-4-[(3~{R},5~{R},8~{R},9~{S},10~{S},12~{S},13~{R},14~{S},1...

MacromoleculeName: (4~{R})-4-[(3~{R},5~{R},8~{R},9~{S},10~{S},12~{S},13~{R},14~{S},17~{R})-10,13-dimethyl-12-oxidanyl-3-phosphonooxy-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1~{H}-cyclopenta[a]phenanthren-17-yl]pentanoic acid
type: ligand / ID: 2 / Number of copies: 1 / Formula: JW0
Molecular weightTheoretical: 472.552 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

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.1 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7s8p

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 451859
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD

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