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- EMDB-34549: Lodoxamide-bound GPR35 in complex with G13 -

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Entry
Database: EMDB / ID: EMD-34549
TitleLodoxamide-bound GPR35 in complex with G13
Map data
Sample
  • Complex: Lodoxamide-GPR35-G13 complex
    • Protein or peptide: Guanine nucleotide-binding protein subunit alpha-13
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: G-protein coupled receptor 35G protein-coupled receptor
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: scFv16
  • Ligand: 2,2'-[(2-chloro-5-cyano-1,3-phenylene)bis(azanediyl)]bis(oxoacetic acid)
  • Ligand: CALCIUM IONCalcium
  • Ligand: CHOLESTEROL
KeywordsGPR35 / G13 / Lodoxamide / MEMBRANE PROTEIN
Function / homology
Function and homology information


negative regulation of neuronal action potential / : / D5 dopamine receptor binding / regulation of fibroblast migration / C-X-C chemokine receptor activity / negative regulation of voltage-gated calcium channel activity / negative regulation of vascular associated smooth muscle cell migration / Class A/1 (Rhodopsin-like receptors) / chemokine-mediated signaling pathway / regulation of small GTPase mediated signal transduction ...negative regulation of neuronal action potential / : / D5 dopamine receptor binding / regulation of fibroblast migration / C-X-C chemokine receptor activity / negative regulation of voltage-gated calcium channel activity / negative regulation of vascular associated smooth muscle cell migration / Class A/1 (Rhodopsin-like receptors) / chemokine-mediated signaling pathway / regulation of small GTPase mediated signal transduction / positive regulation of Rho protein signal transduction / branching involved in blood vessel morphogenesis / NRAGE signals death through JNK / negative regulation of vascular associated smooth muscle cell proliferation / CDC42 GTPase cycle / Rho protein signal transduction / cytoskeleton organization / RAC1 GTPase cycle / guanyl-nucleotide exchange factor activity / G protein-coupled receptor activity / brush border membrane / G-protein beta/gamma-subunit complex binding / 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 / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / platelet activation / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / regulation of blood pressure / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / sensory perception of taste / GPER1 signaling / G-protein beta-subunit binding / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / G alpha (12/13) signalling events / melanosome / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / GTPase binding / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / regulation of cell shape / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / in utero embryonic development / Extra-nuclear estrogen signaling / cell differentiation / G protein-coupled receptor signaling pathway / lysosomal membrane / focal adhesion / GTPase activity / synapse / protein-containing complex binding / GTP binding / signal transduction / extracellular exosome / membrane / metal ion binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
G protein-coupled receptor 35, 7TM / G-protein alpha subunit, group 12/13 / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain ...G protein-coupled receptor 35, 7TM / G-protein alpha subunit, group 12/13 / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / 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. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
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 subunit alpha-13 / G-protein coupled receptor 35
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsYuan Q / Duan J / Liu Q / Xu HE / Jiang Y
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Cell Discov / Year: 2022
Title: Insights into divalent cation regulation and G-coupling of orphan receptor GPR35.
Authors: Jia Duan / Qiufeng Liu / Qingning Yuan / Yujie Ji / Shengnan Zhu / Yangxia Tan / Xinheng He / Youwei Xu / Jingjing Shi / Xi Cheng / Hualiang Jiang / H Eric Xu / Yi Jiang /
Abstract: Endogenous ions play important roles in the function and pharmacology of G protein-coupled receptors (GPCRs) with limited atomic evidence. In addition, compared with G protein subtypes G, G, and G, ...Endogenous ions play important roles in the function and pharmacology of G protein-coupled receptors (GPCRs) with limited atomic evidence. In addition, compared with G protein subtypes G, G, and G, insufficient structural evidence is accessible to understand the coupling mechanism of G protein by GPCRs. Orphan receptor GPR35, which is predominantly expressed in the gastrointestinal tract and is closely related to inflammatory bowel diseases (IBDs), stands out as a prototypical receptor for investigating ionic modulation and G coupling. Here we report a cryo-electron microscopy structure of G-coupled GPR35 bound to an anti-allergic drug, lodoxamide. This structure reveals a novel divalent cation coordination site and a unique ionic regulatory mode of GPR35 and also presents a highly positively charged binding pocket and the complementary electrostatic ligand recognition mode, which explain the promiscuity of acidic ligand binding by GPR35. Structural comparison of the GPR35-G complex with other G protein subtypes-coupled GPCRs reveals a notable movement of the C-terminus of α5 helix of the Gα subunit towards the receptor core and the least outward displacement of the cytoplasmic end of GPR35 TM6. A featured 'methionine pocket' contributes to the G coupling by GPR35. Together, our findings provide a structural basis for divalent cation modulation, ligand recognition, and subsequent G protein coupling of GPR35 and offer a new opportunity for designing GPR35-targeted drugs for the treatment of IBDs.
History
DepositionOct 23, 2022-
Header (metadata) releaseFeb 8, 2023-
Map releaseFeb 8, 2023-
UpdateNov 8, 2023-
Current statusNov 8, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_34549.png

Downloads & links

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Map

FileDownload / File: emd_34549.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.04 Å
Density
Contour LevelBy AUTHOR: 0.3
Minimum - Maximum-0.023889825 - 1.8967957
Average (Standard dev.)0.0014199842 (±0.024882765)
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_34549_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_34549_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 : Lodoxamide-GPR35-G13 complex

EntireName: Lodoxamide-GPR35-G13 complex
Components
  • Complex: Lodoxamide-GPR35-G13 complex
    • Protein or peptide: Guanine nucleotide-binding protein subunit alpha-13
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: G-protein coupled receptor 35G protein-coupled receptor
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: scFv16
  • Ligand: 2,2'-[(2-chloro-5-cyano-1,3-phenylene)bis(azanediyl)]bis(oxoacetic acid)
  • Ligand: CALCIUM IONCalcium
  • Ligand: CHOLESTEROL

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Supramolecule #1: Lodoxamide-GPR35-G13 complex

SupramoleculeName: Lodoxamide-GPR35-G13 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Guanine nucleotide-binding protein subunit alpha-13

MacromoleculeName: Guanine nucleotide-binding protein subunit alpha-13 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 42.423633 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGCTLSAEDK AAVERSKMID KCLSREKTYV KRLVKILLLG AGESGKSTFL KQMRIIHGQD FDQRAREEFR PTIYSNVIKG MRVLVDARE KLHIPWGDNS NQQHGDKMMS FDTRAPMAAQ GMVETRVFLQ YLPAIRALWA DSGIQNAYDR RREFQLGESV K YFLDNLDK ...String:
MGCTLSAEDK AAVERSKMID KCLSREKTYV KRLVKILLLG AGESGKSTFL KQMRIIHGQD FDQRAREEFR PTIYSNVIKG MRVLVDARE KLHIPWGDNS NQQHGDKMMS FDTRAPMAAQ GMVETRVFLQ YLPAIRALWA DSGIQNAYDR RREFQLGESV K YFLDNLDK LGEPDYIPSQ QDILLARRPT KGIHEYDFEI KNVPFKMVDV GGQRSERKRW FECFDSVTSI LFLVSSSEFD QV LMEDRLT NRLTESLNIF ETIVNNRVFS NVSIILFLNK TDLLEEKVQI VSIKDYFLEF EGDPHCLRDV QKFLVECFRN KRR DQQQKP LYHHFTTAIN TENIRLVFRD VKDTILHDNL KQLMLQ

UniProtKB: Guanine nucleotide-binding protein subunit alpha-13

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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: 40.226992 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGSLLQSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD ...String:
MGSLLQSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD TTCALWDIET GQQTTTFTGH TGDVMSLSLA PDTRLFVSGA CDASAKLWDV REGMCRQTFT GHESDINAIC FF PNGNAFA TGSDDATCRL FDLRADQELM TYSHDNIICG ITSVSFSKSG RLLLAGYDDF NCNVWDALKA DRAGVLAGHD NRV SCLGVT DDGMAVATGS WDSFLKIWNG SSGGGGSGGG GSSGVSGWRL FKKIS

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

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Macromolecule #3: G-protein coupled receptor 35

MacromoleculeName: G-protein coupled receptor 35 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 33.972047 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: NGTYNTCGSS DLTWPPAIKL GFYAYLGVLL VLGLLLNSLA LWVFCCRMQQ WTETRIYMTN LAVADLCLLC TLPFVLHSLR DTSDTPLCQ LSQGIYLTNR YMSISLVTAI AVDRYVAVRH PLRARGLRSP RQAAAVCAVL WVLVIGSLVA RWLLGIQEGG F CFRSTRHN ...String:
NGTYNTCGSS DLTWPPAIKL GFYAYLGVLL VLGLLLNSLA LWVFCCRMQQ WTETRIYMTN LAVADLCLLC TLPFVLHSLR DTSDTPLCQ LSQGIYLTNR YMSISLVTAI AVDRYVAVRH PLRARGLRSP RQAAAVCAVL WVLVIGSLVA RWLLGIQEGG F CFRSTRHN FNSMAFPLLG FYLPLAVVVF CSLKVVTALA QRPPTDVGQA EATRKAARMV WANLLVFVVC FLPLHVGLTV RL AVGWNAC ALLETIRRAL YITSKLSDAN CCLDAICYYY MAKEFQEASA LAVAPSAKAH KSQDSLCVTL A

UniProtKB: G-protein coupled receptor 35

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Macromolecule #4: 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: 4 / 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 #5: scFv16

MacromoleculeName: scFv16 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 26.277299 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS AGGGGSGGGG SGGGGSADIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String:
VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS AGGGGSGGGG SGGGGSADIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL

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Macromolecule #6: 2,2'-[(2-chloro-5-cyano-1,3-phenylene)bis(azanediyl)]bis(oxoaceti...

MacromoleculeName: 2,2'-[(2-chloro-5-cyano-1,3-phenylene)bis(azanediyl)]bis(oxoacetic acid)
type: ligand / ID: 6 / Number of copies: 1 / Formula: WYB
Molecular weightTheoretical: 311.635 Da
Chemical component information

ChemComp-WYB:
2,2'-[(2-chloro-5-cyano-1,3-phenylene)bis(azanediyl)]bis(oxoacetic acid)

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Macromolecule #7: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 7 / Number of copies: 1 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #8: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 8 / Number of copies: 3 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL / Cholesterol

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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: 7.04
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 591246

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