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- EMDB-51324: Cryo-EM structure of Thromboxane A2 receptor-miniGq protein compl... -

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Entry
Database: EMDB / ID: EMD-51324
TitleCryo-EM structure of Thromboxane A2 receptor-miniGq protein complex bound to U46619
Map datasharpened composite cryo-EM map of Thromboxane A2 receptor-Gq Protein Complex bound to U46619
Sample
  • Complex: Thromboxane A2 receptor-Gq Protein Complex
    • Protein or peptide: Thromboxane A2 receptor
    • Protein or peptide: Engineered miniGq
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
  • Ligand: (5Z)-7-{(1R,4S,5S,6R)-6-[(1E,3S)-3-hydroxyoct-1-en-1-yl]-2-oxabicyclo[2.2.1]hept-5-yl}hept-5-enoic acid
  • Ligand: CHOLESTEROL
KeywordsSingle particle cryo-EM / GPCR / G-proteins / MEMBRANE PROTEIN
Function / homology
Function and homology information


thromboxane A2 receptor activity / Prostanoid ligand receptors / positive regulation of smooth muscle contraction / positive regulation of blood pressure / negative regulation of cell migration involved in sprouting angiogenesis / response to testosterone / smooth muscle contraction / positive regulation of vasoconstriction / positive regulation of blood coagulation / response to nutrient ...thromboxane A2 receptor activity / Prostanoid ligand receptors / positive regulation of smooth muscle contraction / positive regulation of blood pressure / negative regulation of cell migration involved in sprouting angiogenesis / response to testosterone / smooth muscle contraction / positive regulation of vasoconstriction / positive regulation of blood coagulation / response to nutrient / acrosomal vesicle / guanyl-nucleotide exchange factor activity / Olfactory Signaling Pathway / positive regulation of angiogenesis / 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 / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / 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 / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / 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 / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / 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 / G-protein beta-subunit binding / cellular response to prostaglandin E stimulus / heterotrimeric G-protein complex / G alpha (12/13) signalling events / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / sensory perception of taste / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / positive regulation of cytosolic calcium ion concentration / retina development in camera-type eye / cellular response to lipopolysaccharide / 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 / response to ethanol / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / nuclear speck / G protein-coupled receptor signaling pathway / response to xenobiotic stimulus / inflammatory response / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Thromboxane receptor / Prostanoid receptor / 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 ...Thromboxane receptor / Prostanoid receptor / 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. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 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
Similarity search - Domain/homology
Thromboxane A2 receptor / 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
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.26 Å
AuthorsMatzov D / Krawinski P / Caffrey M / Shalev Benami M
Funding supportEuropean Union, 1 items
OrganizationGrant numberCountry
European Research Council (ERC)949364European Union
CitationJournal: Nat Commun / Year: 2026
Title: Structural and dynamic insights into agonist recognition and function of the thromboxane A receptor.
Authors: Pawel Krawinski / Donna Matzov / Aoife Ryder / Kanhaya Lal / Dmitry S Karlov / Georges Chalhoub / Eamon P Mulvaney / B Therese Kinsella / Peter J McCormick / Martin Caffrey / Irina G ...Authors: Pawel Krawinski / Donna Matzov / Aoife Ryder / Kanhaya Lal / Dmitry S Karlov / Georges Chalhoub / Eamon P Mulvaney / B Therese Kinsella / Peter J McCormick / Martin Caffrey / Irina G Tikhonova / Moran Shalev-Benami /
Abstract: The thromboxane A receptor (TP), expressed in platelets and smooth muscle, plays an important role in blood clotting and muscle contraction. The endogenous ligand of this G protein-coupled receptor ...The thromboxane A receptor (TP), expressed in platelets and smooth muscle, plays an important role in blood clotting and muscle contraction. The endogenous ligand of this G protein-coupled receptor (GPCR), thromboxane A (TXA), is a short-lived arachidonic acid metabolite with a half-life of ∼30 seconds, which makes investigating the TP structure and activation mechanism highly challenging. Here we determine the structures of the TP in complex with the synthetic agonists, U46619 and I-BOP, stable analogues of the natural ligand, in the presence of the signalling protein partner, G. The structures reveal a unique activation switch for the receptor that differs from typical class A GPCR family members. Complemented by functional studies, mutational analysis, docking, and molecular dynamics (MD) simulations, our investigation highlights the differences between agonist and antagonist binding and explores the ligand entry mechanism to the binding pocket from within the membrane via a molecular gate composed of two transmembrane helices. In addition, our study provides crucial information to aid in the rational design of compounds targeting the TP, and offers mechanistic insights into inherited disorders associated with mutations in the TP.
History
DepositionAug 13, 2024-
Header (metadata) releaseAug 27, 2025-
Map releaseAug 27, 2025-
UpdateMar 11, 2026-
Current statusMar 11, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_51324.png

Downloads & links

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Map

FileDownload / File: emd_51324.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened composite cryo-EM map of Thromboxane A2 receptor-Gq Protein Complex bound to U46619
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 360 pix.
= 303.228 Å		0.84 Å/pix.
x 360 pix.
= 303.228 Å		0.84 Å/pix.
x 360 pix.
= 303.228 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8423 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.25
Minimum - Maximum-1.936759 - 2.9195495
Average (Standard dev.)-0.00087193755 (±0.036700588)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 303.228 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: composite cryo-EM map of Thromboxane A2 receptor-Gq Protein...

Fileemd_51324_additional_1.map
Annotationcomposite cryo-EM map of Thromboxane A2 receptor-Gq Protein Complex bound to U46619
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Thromboxane A2 receptor-Gq Protein Complex

EntireName: Thromboxane A2 receptor-Gq Protein Complex
Components
  • Complex: Thromboxane A2 receptor-Gq Protein Complex
    • Protein or peptide: Thromboxane A2 receptor
    • Protein or peptide: Engineered miniGq
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
  • Ligand: (5Z)-7-{(1R,4S,5S,6R)-6-[(1E,3S)-3-hydroxyoct-1-en-1-yl]-2-oxabicyclo[2.2.1]hept-5-yl}hept-5-enoic acid
  • Ligand: CHOLESTEROL

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Supramolecule #1: Thromboxane A2 receptor-Gq Protein Complex

SupramoleculeName: Thromboxane A2 receptor-Gq Protein Complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Thromboxane A2 receptor

MacromoleculeName: Thromboxane A2 receptor / type: protein_or_peptide / ID: 1 / Details: Thromboxane A2 receptor / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.462969 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MWPNGSSLGP CFRPTNITLE ERRLIASPWF AASFCVVGLA SNLLALSVLA GARQGGSHTR SSFLTFLCGL VLTDFLGLLV TGTIVVSQH AALFEWHAVD PGCRLCRFMG VVMIFFGLSP LLLGAAMASE RYLGITRPFS RPAVASQRRA WATVGLVWAA A LALGLLPL ...String:
MWPNGSSLGP CFRPTNITLE ERRLIASPWF AASFCVVGLA SNLLALSVLA GARQGGSHTR SSFLTFLCGL VLTDFLGLLV TGTIVVSQH AALFEWHAVD PGCRLCRFMG VVMIFFGLSP LLLGAAMASE RYLGITRPFS RPAVASQRRA WATVGLVWAA A LALGLLPL LGVGRYTVQY PGSWCFLTLG AESGDVAFGL LFSMLGGLSV GLSFLLNTVS VATLCHVYHG QEAAQQRPRD SE VEMMAQL LGIMVVASVC WLPLLVFIAQ TVLRNPPAMS PAGQLSRTTE KELLIYLRVA TWNQILDPWV YILFRRAVLR RLQ PRLSTR PRSLSLQPQL TQRSGLQ

UniProtKB: Thromboxane A2 receptor

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Macromolecule #2: Engineered miniGq

MacromoleculeName: Engineered miniGq / type: protein_or_peptide / ID: 2 / Details: Mini Gq / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 28.084832 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: 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

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Macromolecule #3: 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: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.41693 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL ...String:
MSELDQLRQE 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

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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: (5Z)-7-{(1R,4S,5S,6R)-6-[(1E,3S)-3-hydroxyoct-1-en-1-yl]-2-oxabic...

MacromoleculeName: (5Z)-7-{(1R,4S,5S,6R)-6-[(1E,3S)-3-hydroxyoct-1-en-1-yl]-2-oxabicyclo[2.2.1]hept-5-yl}hept-5-enoic acid
type: ligand / ID: 5 / Number of copies: 1 / Formula: PUC
Molecular weightTheoretical: 350.492 Da
Chemical component information

ChemComp-PUC:
(5Z)-7-{(1R,4S,5S,6R)-6-[(1E,3S)-3-hydroxyoct-1-en-1-yl]-2-oxabicyclo[2.2.1]hept-5-yl}hept-5-enoic acid

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Macromolecule #6: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 6 / Number of copies: 4 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
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: 7.5
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 90 sec.
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 38.4 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 20.0 µm / Nominal defocus min: 8.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.26 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 216383
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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