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- PDB-8kex: CryoEM structure of Gq coupled MRGPRX4 with agonist DCA-3P, local -

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Basic information

Entry
Database: PDB / ID: 8kex
TitleCryoEM structure of Gq coupled MRGPRX4 with agonist DCA-3P, local
ComponentsSoluble cytochrome b562,Mas-related G-protein coupled receptor member X4,Green fluorescent protein
KeywordsMEMBRANE PROTEIN / MRGPRX4 / Bile acid / Cholestatic itch / GPCR / Agonist
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 speciesEscherichia coli (E. coli)
Homo sapiens (human)
Aequorea victoria (jellyfish)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsYang, J. / Fan, J.P. / Lei, X.G.
Funding support China, 1items
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, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Nov 6, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 13, 2024Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update
Revision 1.2Nov 27, 2024Group: Data collection / Category: em_admin / Item: _em_admin.last_update
Revision 1.3Dec 25, 2024Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)80,2682
Polymers79,7961
Non-polymers4731
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,Green fluorescent protein / Cytochrome b-562 / Sensory neuron-specific G-protein coupled receptor 5/6


Mass: 79795.680 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. exp.) Aequorea victoria (jellyfish)
Gene: cybC, MRGPRX4, MRGX4, SNSR5, SNSR6, GFP / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P0ABE7, UniProt: Q96LA9, UniProt: P42212
#2: Chemical ChemComp-JW0 / (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


Mass: 472.552 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H41O7P / 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: Cryo-EM structure of MRGPRX4 complex with agonist DCA-3P
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
31Escherichia coli (E. coli)562
41Aequorea victoria (jellyfish)6100
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1100 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 451859 / Symmetry type: POINT

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