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Open data
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Basic information
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Title | CryoEM structure of Gq coupled MRGPRX4 with agonist DCA-3P | |||||||||
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![]() | MRGPRX4 / Bile acid / Cholestatic itch / GPCR / Agonist / MEMBRANE PROTEIN | |||||||||
Function / homology | ![]() bioluminescence / generation of precursor metabolites and energy / electron transport chain / G protein-coupled receptor activity / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway ...bioluminescence / generation of precursor metabolites and energy / electron transport chain / G protein-coupled receptor activity / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / Ca2+ pathway / retina development in camera-type eye / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Ras protein signal transduction / periplasmic space / electron transfer activity / Extra-nuclear estrogen signaling / cell population proliferation / G protein-coupled receptor signaling pathway / iron ion binding / lysosomal membrane / GTPase activity / synapse / heme binding / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytosol / cytoplasm Similarity search - Function | |||||||||
Biological species | ![]() ![]() ![]() ![]() ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.9 Å | |||||||||
![]() | Yang J / Fan JP / Lei XG | |||||||||
Funding support | ![]()
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![]() | ![]() 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. | |||||||||
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 59.7 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 20.1 KB 20.1 KB | Display Display | ![]() |
Images | ![]() | 24.6 KB | ||
Filedesc metadata | ![]() | 7.1 KB | ||
Others | ![]() ![]() | 59.3 MB 59.3 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8k4sMC ![]() 8kexC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.04 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_36890_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_36890_half_map_2.map | ||||||||||||
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Density Histograms |
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Sample components
-Entire : Complex of MRGPRX4 with Gq and agonist DCA-3P
Entire | Name: Complex of MRGPRX4 with Gq and agonist DCA-3P |
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Components |
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-Supramolecule #1: Complex of MRGPRX4 with Gq and agonist DCA-3P
Supramolecule | Name: Complex of MRGPRX4 with Gq and agonist DCA-3P / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #2-#5, #1 |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: Soluble cytochrome b562,Mas-related G-protein coupled receptor me...
Macromolecule | Name: Soluble cytochrome b562,Mas-related G-protein coupled receptor member X4,Green fluorescent protein type: protein_or_peptide / ID: 1 Details: The domain (1-8) is corresponding to Flag-tag. The doamin (9-116) is corresponding to Soluble cytochrome b562. The domain (117-438) is corresponding to MRGPRX4 (GenBank: AY042216.1). The ...Details: The domain (1-8) is corresponding to Flag-tag. The doamin (9-116) is corresponding to Soluble cytochrome b562. The domain (117-438) is corresponding to MRGPRX4 (GenBank: AY042216.1). The domain (439-710) is corresponding to HRV 3C site and GFP. Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 79.79568 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: 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 |
-Macromolecule #2: Gs-mini-Gq chimera
Macromolecule | Name: Gs-mini-Gq chimera / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 28.084832 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: 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 |
-Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 37.342785 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: GSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL ...String: GSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KLWDVREGMC RQTFTGHESD INAICFFPNG NA FATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAGHDNRVSC LGV TDDGMA VATGSWDSFL KIWN UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 8.506765 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI LGSAGSAGSA UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-Macromolecule #5: scFv16
Macromolecule | Name: scFv16 / type: protein_or_peptide / ID: 5 Details: Author stated: the domain (3-254) is corresponding to this scFv16 (1-252 amino acids). Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 26.955045 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: GSMDVQLVES GGGLVQPGGS RKLSCSASGF AFSSFGMHWV RQAPEKGLEW VAYISSGSGT IYYADTVKGR FTISRDDPKN TLFLQMTSL RSEDTAMYYC VRSIYYYGSS PFDFWGQGTT LTVSSGGGGS GGGGSGGGGS DIVMTQATSS VPVTPGESVS I SCRSSKSL ...String: GSMDVQLVES GGGLVQPGGS RKLSCSASGF AFSSFGMHWV RQAPEKGLEW VAYISSGSGT IYYADTVKGR FTISRDDPKN TLFLQMTSL RSEDTAMYYC VRSIYYYGSS PFDFWGQGTT LTVSSGGGGS GGGGSGGGGS DIVMTQATSS VPVTPGESVS I SCRSSKSL LHSNGNTYLY WFLQRPGQSP QLLIYRMSNL ASGVPDRFSG SGSGTAFTLT ISRLEAEDVG VYYCMQHLEY PL TFGAGTK LELKAAA |
-Macromolecule #6: (4~{R})-4-[(3~{R},5~{R},8~{R},9~{S},10~{S},12~{S},13~{R},14~{S},1...
Macromolecule | Name: (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: 6 / Number of copies: 1 / Formula: JW0 |
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Molecular weight | Theoretical: 472.552 Da |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination 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 model | Type of model: PDB ENTRY PDB model - PDB ID: |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 451859 |
Initial angle assignment | Type: RANDOM ASSIGNMENT |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |