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- EMDB-60050: Cryo-EM structure of the receptor of xGPR4-Gs complex in pH6.2 -

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Basic information

Entry
Database: EMDB / ID: EMD-60050
TitleCryo-EM structure of the receptor of xGPR4-Gs complex in pH6.2
Map data
Sample
  • Complex: Cryo-EM structure of the receptor of xGPR4-Gs complex in pH6.2
    • Protein or peptide: G-protein coupled receptor 4
KeywordspH6.2 / xGPR4 / receptor / MEMBRANE PROTEIN/IMMUNE SYSTEM / MEMBRANE PROTEIN
Function / homology
Function and homology information


cellular response to acidic pH / PKA activation in glucagon signalling / developmental growth / hair follicle placode formation / D1 dopamine receptor binding / intracellular transport / vascular endothelial cell response to laminar fluid shear stress / renal water homeostasis / activation of adenylate cyclase activity / Hedgehog 'off' state ...cellular response to acidic pH / PKA activation in glucagon signalling / developmental growth / hair follicle placode formation / D1 dopamine receptor binding / intracellular transport / vascular endothelial cell response to laminar fluid shear stress / renal water homeostasis / activation of adenylate cyclase activity / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / cellular response to glucagon stimulus / regulation of insulin secretion / adenylate cyclase activator activity / trans-Golgi network membrane / negative regulation of inflammatory response to antigenic stimulus / G protein-coupled receptor activity / bone development / platelet aggregation / G-protein beta/gamma-subunit complex binding / cognition / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / 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 / photoreceptor disc membrane / 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 / sensory perception of smell / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / 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) / positive regulation of cold-induced thermogenesis / retina development in camera-type eye / G protein activity / GTPase binding / Ca2+ pathway / fibroblast proliferation / 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 / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / GTP binding / protein-containing complex binding / signal transduction / extracellular exosome / metal ion binding / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
G protein-coupled receptor 4 orphan / G-protein alpha subunit, group S / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain ...G protein-coupled receptor 4 orphan / G-protein alpha subunit, group S / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / 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 / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / 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) / 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 / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
G-protein coupled receptor 4 / 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 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Similarity search - Component
Biological speciesXenopus tropicalis (tropical clawed frog)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.05 Å
AuthorsRong NK / Wen X / Yang F / Sun JP
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81773704 China
CitationJournal: Cell / Year: 2025
Title: Evolutionary study and structural basis of proton sensing by Mus GPR4 and Xenopus GPR4.
Authors: Xin Wen / Pan Shang / Haidi Chen / Lulu Guo / Naikang Rong / Xiaoyu Jiang / Xuan Li / Junyan Liu / Gongming Yang / Jiacheng Zhang / Kongkai Zhu / Qingbiao Meng / Xuefei He / Zhihai Wang / ...Authors: Xin Wen / Pan Shang / Haidi Chen / Lulu Guo / Naikang Rong / Xiaoyu Jiang / Xuan Li / Junyan Liu / Gongming Yang / Jiacheng Zhang / Kongkai Zhu / Qingbiao Meng / Xuefei He / Zhihai Wang / Zili Liu / Haoran Cheng / Yilin Zheng / Bifei Zhang / Jiaojiao Pang / Zhaoqian Liu / Peng Xiao / Yuguo Chen / Lunxu Liu / Fengming Luo / Xiao Yu / Fan Yi / Pengju Zhang / Fan Yang / Cheng Deng / Jin-Peng Sun /
Abstract: Animals have evolved pH-sensing membrane receptors, such as G-protein-coupled receptor 4 (GPR4), to monitor pH changes related to their physiology and generate adaptive reactions. However, the ...Animals have evolved pH-sensing membrane receptors, such as G-protein-coupled receptor 4 (GPR4), to monitor pH changes related to their physiology and generate adaptive reactions. However, the evolutionary trajectory and structural mechanism of proton sensing by GPR4 remain unresolved. Here, we observed a positive correlation between the optimal pH of GPR4 activity and the blood pH range across different species. By solving 7-cryoelectron microscopy (cryo-EM) structures of Xenopus tropicalis GPR4 (xtGPR4) and Mus musculus GPR4 (mmGPR4) under varying pH conditions, we identified that protonation of H and H enabled polar network establishment and tighter association between the extracellular loop 2 (ECL2) and 7 transmembrane (7TM) domain, as well as a conserved propagating path, which are common mechanisms underlying protonation-induced GPR4 activation across different species. Moreover, protonation of distinct extracellular H contributed to the more acidic optimal pH range of xtGPR4. Overall, our study revealed common and distinct mechanisms of proton sensing by GPR4, from a structural, functional, and evolutionary perspective.
History
DepositionMay 7, 2024-
Header (metadata) releaseFeb 26, 2025-
Map releaseFeb 26, 2025-
UpdateJul 23, 2025-
Current statusJul 23, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_60050.png

Downloads & links

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Map

FileDownload / File: emd_60050.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 300 pix.
= 279. Å		0.93 Å/pix.
x 300 pix.
= 279. Å		0.93 Å/pix.
x 300 pix.
= 279. Å

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.93 Å
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Histogram

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Contour LevelBy AUTHOR: 0.01
Minimum - Maximum-0.013235921 - 2.8465824
Average (Standard dev.)0.00036518875 (±0.015400711)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 279.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_60050_msk_1.map
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Half map: #1

Fileemd_60050_half_map_1.map
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Half map: #2

Fileemd_60050_half_map_2.map
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Sample components

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Entire : Cryo-EM structure of the receptor of xGPR4-Gs complex in pH6.2

EntireName: Cryo-EM structure of the receptor of xGPR4-Gs complex in pH6.2
Components
  • Complex: Cryo-EM structure of the receptor of xGPR4-Gs complex in pH6.2
    • Protein or peptide: G-protein coupled receptor 4

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Supramolecule #1: Cryo-EM structure of the receptor of xGPR4-Gs complex in pH6.2

SupramoleculeName: Cryo-EM structure of the receptor of xGPR4-Gs complex in pH6.2
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Xenopus tropicalis (tropical clawed frog)

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Macromolecule #1: G-protein coupled receptor 4

MacromoleculeName: G-protein coupled receptor 4 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Xenopus tropicalis (tropical clawed frog)
Molecular weightTheoretical: 38.083359 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSNFTPDACN VDSGLDSVLP PSLYALVFTL GLPANLLALW AAWLQVRKGR ELGVYLLNLS LSDLLLICAL PPWTDYYLRR DVWGYGPGA CRLFGFVFYT NLYVGAAFLS CVSADRYLAV AHPLRFPGAR PIRSAAAVSA LIWMLELAAN APPLLGEAIH R DRYNHTFC ...String:
MSNFTPDACN VDSGLDSVLP PSLYALVFTL GLPANLLALW AAWLQVRKGR ELGVYLLNLS LSDLLLICAL PPWTDYYLRR DVWGYGPGA CRLFGFVFYT NLYVGAAFLS CVSADRYLAV AHPLRFPGAR PIRSAAAVSA LIWMLELAAN APPLLGEAIH R DRYNHTFC YESYPLSGRG AALANVGRVL AGFLLPWGVM MLCYAGLLRA LRGSASCEQR ERRRVRRLAL GLPCVALLCY GP YHALLLL RSLVFLVGGG SVDAGGGCAL EERLFPAYHA SLALATLNCL ADPALYCLAC PGARGEVAKV VGGVVAWAMG KER RAWGER GGNGRGCGEG EEVGMVELRG NGREFVV

UniProtKB: G-protein coupled receptor 4

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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: 6.2
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 1.875 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: DIFFRACTION / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.05 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 640581
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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