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- EMDB-65349: Structure of hTRPA1 complexed with LIQA -

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Basic information

Entry
Database: EMDB / ID: EMD-65349
TitleStructure of hTRPA1 complexed with LIQA
Map data
Sample
  • Complex: hTRPA1 complex with inhibitor LIQA
    • Protein or peptide: Transient receptor potential cation channel subfamily A member 1
  • Ligand: Liquiritin apioside
KeywordsInhibitor / Complex / Ion channel / MEMBRANE PROTEIN
Function / homology
Function and homology information


regulation of blood circulation / positive regulation of monoatomic anion transport / cellular response to food / temperature-gated cation channel activity / regulation of neuronal action potential / cellular response to carbon dioxide / osmolarity-sensing monoatomic cation channel activity / detection of mechanical stimulus involved in sensory perception / stereocilium bundle / detection of chemical stimulus involved in sensory perception of pain ...regulation of blood circulation / positive regulation of monoatomic anion transport / cellular response to food / temperature-gated cation channel activity / regulation of neuronal action potential / cellular response to carbon dioxide / osmolarity-sensing monoatomic cation channel activity / detection of mechanical stimulus involved in sensory perception / stereocilium bundle / detection of chemical stimulus involved in sensory perception of pain / urinary bladder smooth muscle contraction / thermoception / cellular response to toxic substance / cellular response to caffeine / calcium ion transmembrane import into cytosol / cellular response to cold / TRP channels / intracellularly gated calcium channel activity / voltage-gated calcium channel activity / monoatomic ion transport / sensory perception of pain / response to cold / positive regulation of insulin secretion involved in cellular response to glucose stimulus / cellular response to hydrogen peroxide / intracellular calcium ion homeostasis / calcium channel activity / calcium ion transmembrane transport / cellular response to heat / channel activity / protein homotetramerization / cell surface receptor signaling pathway / apical plasma membrane / axon / identical protein binding / plasma membrane
Similarity search - Function
: / Ankyrin repeats (many copies) / Ankyrin repeat / Ankyrin repeat profile. / Ankyrin repeats (3 copies) / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Transient receptor potential cation channel subfamily A member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.59 Å
AuthorsMin YM / Zonglin DZ / Yang YY
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Phytomedicine / Year: 2026
Title: Structural insights into TRPA1 and TRPV1 modulation by flavonoid glycosides from licorice for cough relief.
Authors: Yang Yi / Guifang Duan / Zonglin Dai / Xiaogang Zhou / Jian Huang / Zhengtong Jin / Ao Yang / Yue Li / Zhuo Huang / Min Ye /
Abstract: BACKGROUND: Transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) are two nociceptive TRP channel subtypes that play central roles in cough hypersensitivity.
PURPOSE: This study evaluated the antitussive efficacy of liquiritin apioside (LIQA) and liquiritin (LIQ), two major flavonoid glycosides from licorice, in acute chemically induced cough models, and ...PURPOSE: This study evaluated the antitussive efficacy of liquiritin apioside (LIQA) and liquiritin (LIQ), two major flavonoid glycosides from licorice, in acute chemically induced cough models, and investigated their modulations of TRPA1 and TRPV1.
METHODS: In guinea pig models, cough was induced by capsaicin (a TRPV1 agonist) and cinnamaldehyde (a TRPA1 agonist), respectively. The inhibitory effects of LIQA and LIQ against TRPA1 and TRPV1 were ...METHODS: In guinea pig models, cough was induced by capsaicin (a TRPV1 agonist) and cinnamaldehyde (a TRPA1 agonist), respectively. The inhibitory effects of LIQA and LIQ against TRPA1 and TRPV1 were assessed using electrophysiological profiling and fluorescence-based calcium assays. To elucidate the underlying mechanisms, high-resolution cryo-electron microscopy (cryo-EM) structural analysis, and molecular simulations were conducted.
RESULTS: LIQA and LIQ significantly reduced cough frequency in the guinea pig models. Electrophysiological profiling revealed that LIQA suppressed human TRPA1 (hTRPA1) channel activity, while LIQ ...RESULTS: LIQA and LIQ significantly reduced cough frequency in the guinea pig models. Electrophysiological profiling revealed that LIQA suppressed human TRPA1 (hTRPA1) channel activity, while LIQ blocked human TRPV1 (hTRPV1) activation. High-resolution cryo-EM structures of hTRPA1/LIQA (2.59 Å) and hTRPV1/LIQ (3.05 Å) complexes were obtained. Structural analysis indicates that LIQA stabilizes hTRPA1 in a closed conformation with T624 at the coupling region site, whereas LIQ interacts with S512 through hydrogen bonding in the deep S4-S5 site of hTRPV1, thereby inhibiting pore opening.
CONCLUSION: This study establishes LIQA and LIQ as lead compounds with acute antitussive activities mediated by TRPA1/TRPV1 modulation.
History
DepositionJul 12, 2025-
Header (metadata) releaseJul 15, 2026-
Map releaseJul 15, 2026-
UpdateJul 15, 2026-
Current statusJul 15, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_65349.png

Downloads & links

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Map

FileDownload / File: emd_65349.map.gz / Format: CCP4 / Size: 209.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.81 Å/pix.
x 380 pix.
= 307.04 Å		0.81 Å/pix.
x 380 pix.
= 307.04 Å		0.81 Å/pix.
x 380 pix.
= 307.04 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.808 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.14
Minimum - Maximum-0.95215225 - 1.4943718
Average (Standard dev.)0.0008650524 (±0.04005568)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions380380380
Spacing380380380
CellA=B=C: 307.04 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_65349_half_map_1.map
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Half map: #2

Fileemd_65349_half_map_2.map
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Sample components

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Entire : hTRPA1 complex with inhibitor LIQA

EntireName: hTRPA1 complex with inhibitor LIQA
Components
  • Complex: hTRPA1 complex with inhibitor LIQA
    • Protein or peptide: Transient receptor potential cation channel subfamily A member 1
  • Ligand: Liquiritin apioside

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Supramolecule #1: hTRPA1 complex with inhibitor LIQA

SupramoleculeName: hTRPA1 complex with inhibitor LIQA / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Transient receptor potential cation channel subfamily A member 1

MacromoleculeName: Transient receptor potential cation channel subfamily A member 1
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 127.66057 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MKRSLRKMWR PGEKKEPQGV VYEDVPDDTE DFKESLKVVF EGSAYGLQNF NKQKKLKRCD DMDTFFLHYA AAEGQIELME KITRDSSLE VLHEMDDYGN TPLHCAVEKN QIESVKFLLS RGANPNLRNF NMMAPLHIAV QGMNNEVMKV LLEHRTIDVN L EGENGNTA ...String:
MKRSLRKMWR PGEKKEPQGV VYEDVPDDTE DFKESLKVVF EGSAYGLQNF NKQKKLKRCD DMDTFFLHYA AAEGQIELME KITRDSSLE VLHEMDDYGN TPLHCAVEKN QIESVKFLLS RGANPNLRNF NMMAPLHIAV QGMNNEVMKV LLEHRTIDVN L EGENGNTA VIIACTTNNS EALQILLKKG AKPCKSNKWG CFPIHQAAFS GSKECMEIIL RFGEEHGYSR QLHINFMNNG KA TPLHLAV QNGDLEMIKM CLDNGAQIDP VEKGRCTAIH FAATQGATEI VKLMISSYSG SVDIVNTTDG CHETMLHRAS LFD HHELAD YLISVGADIN KIDSEGRSPL ILATASASWN IVNLLLSKGA QVDIKDNFGR NFLHLTVQQP YGLKNLRPEF MQMQ QIKEL VMDEDNDGCT PLHYACRQGG PGSVNNLLGF NVSIHSKSKD KKSPLHFAAS YGRINTCQRL LQDISDTRLL NEGDL HGMT PLHLAAKNGH DKVVQLLLKK GALFLSDHNG WTALHHASMG GYTQTMKVIL DTNLKCTDRL DEDGNTALHF AAREGH AKA VALLLSHNAD IVLNKQQASF LHLALHNKRK EVVLTIIRSK RWDECLKIFS HNSPGNKCPI TEMIEYLPEC MKVLLDF CM LHSTEDKSCR DYYIEYNFKY LQCPLEFTKK TPTQDVIYEP LTALNAMVQN NRIELLNHPV CKEYLLMKWL AYGFRAHM M NLGSYCLGLI PMTILVVNIK PGMAFNSTGI INETSDHSEI LDTTNSYLIK TCMILVFLSS IFGYCKEAGQ IFQQKRNYF MDISNVLEWI IYTTGIIFVL PLFVEIPAHL QWQCGAIAVY FYWMNFLLYL QRFENCGIFI VMLEVILKTL LRSTVVFIFL LLAFGLSFY ILLNLQDPFS SPLLSIIQTF SMMLGDINYR ESFLEPYLRN ELAHPVLSFA QLVSFTIFVP IVLMNLLIGL A VGDIAEVQ KHASLKRIAM QVELHTSLEK KLPLWFLRKV DQKSTIVYPN KPRSGGMLFH IFCFLFCTGE IRQEIPNADK SL EMEILKQ KYRLKDLTFL LEKQHELIKL IIQKMEIISE TEDDDSHCSF QDRFKKEQME QRNSRWNTVL RAVKAKTHHL EP

UniProtKB: Transient receptor potential cation channel subfamily A member 1

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Macromolecule #2: Liquiritin apioside

MacromoleculeName: Liquiritin apioside / type: ligand / ID: 2 / Number of copies: 4 / Formula: A1ETS
Molecular weightTheoretical: 550.509 Da

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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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.6 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: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.59 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 106614
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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