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- EMDB-63715: Cryo-EM structure of the human TRPA1 ion channel in complex with ... -

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Basic information

Entry
Database: EMDB / ID: EMD-63715
TitleCryo-EM structure of the human TRPA1 ion channel in complex with crotalphine.
Map dataThe cryo-EM map of the human TRPA1 ion channel in complex with crotalphine
Sample
  • Complex: transient receptor potential cation channel subfamily A member 1
    • Protein or peptide: Transient receptor potential cation channel subfamily A member 1
KeywordsTRANSPORT PROTEIN / 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 / stereocilium bundle / detection of chemical stimulus involved in sensory perception of pain / urinary bladder smooth muscle contraction ...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 / 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 / response to pain / TRP channels / calcium ion transmembrane import into cytosol / cellular response to cold / intracellularly gated calcium channel activity / detection of mechanical stimulus involved in sensory perception of pain / positive regulation of insulin secretion involved in cellular response to glucose stimulus / voltage-gated calcium channel activity / monoatomic ion transport / sensory perception of pain / response to cold / calcium ion transmembrane transport / calcium channel activity / cellular response to hydrogen peroxide / intracellular calcium ion homeostasis / cellular response to heat / channel activity / protein homotetramerization / cell surface receptor signaling pathway / apical plasma membrane / response to xenobiotic stimulus / axon / identical protein binding / plasma membrane
Similarity search - Function
: / Ankyrin repeat / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / 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: 3.81 Å
AuthorsKang MM / Zhang YM / Ding XF / Wang LJ / Sun WY / Jiang H / Chen D / Xu JF / Pang XY
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Membranes (Basel) / Year: 2025
Title: Binding and Activating of Analgesic Crotalphine with Human TRPA1.
Authors: Mingmin Kang / Yanming Zhang / Xiufang Ding / Jianfu Xu / Xiaoyun Pang /
Abstract: TRPA1 (Transient Receptor Potential Ankyrin 1), a cation channel predominantly expressed in sensory neurons, plays a critical role in detecting noxious stimuli and mediating pain signal transmission. ...TRPA1 (Transient Receptor Potential Ankyrin 1), a cation channel predominantly expressed in sensory neurons, plays a critical role in detecting noxious stimuli and mediating pain signal transmission. As a key player in nociceptive signaling pathways, TRPA1 has emerged as a promising therapeutic target for the development of novel analgesics. Crotalphine (CRP), a 14-amino acid peptide, has been demonstrated to specifically activate TRPA1 and elicit potent analgesic effects. Previous cryo-EM (cryo-electron microscopy) studies have elucidated the structural mechanisms of TRPA1 activation by small-molecule agonists, such as iodoacetamide (IA), through covalent modification of N-terminal cysteine residues. However, the molecular interactions between TRPA1 and peptide ligands, including crotalphine, remain unclear. Here, we present the cryo-EM structure of ligand-free human TRPA1 consistent with the literature, as well as TRPA1 complexed with crotalphine, with resolutions of 3.1 Å and 3.8 Å, respectively. Through a combination of single-particle cryo-EM studies, patch-clamp electrophysiology, and microscale thermophoresis (MST), we have identified the cysteine residue at position 621 (Cys621) within the TRPA1 ion channel as the primary binding site for crotalphine. Upon binding to the reactive pocket containing C621, crotalphine induces rotational and translational movements of the transmembrane domain. This allosteric modulation coordinately dilates both the upper and lower gates, facilitating ion permeation.
History
DepositionMar 12, 2025-
Header (metadata) releaseOct 29, 2025-
Map releaseOct 29, 2025-
UpdateOct 29, 2025-
Current statusOct 29, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_63715.png

Downloads & links

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Map

FileDownload / File: emd_63715.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationThe cryo-EM map of the human TRPA1 ion channel in complex with crotalphine
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.04 Å/pix.
x 256 pix.
= 266.24 Å		1.04 Å/pix.
x 256 pix.
= 266.24 Å		1.04 Å/pix.
x 256 pix.
= 266.24 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.04 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.25
Minimum - Maximum-1.4864156 - 1.8465952
Average (Standard dev.)0.0044208067 (±0.06315239)
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: The half Bmap of the human TRPA1 ion channel...

Fileemd_63715_half_map_1.map
AnnotationThe half_Bmap of the human TRPA1 ion channel in complex with crotalphine
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: The half A map of the human TRPA1 ion...

Fileemd_63715_half_map_2.map
AnnotationThe half_A map of the human TRPA1 ion channel in complex with crotalphine
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : transient receptor potential cation channel subfamily A member 1

EntireName: transient receptor potential cation channel subfamily A member 1
Components
  • Complex: transient receptor potential cation channel subfamily A member 1
    • Protein or peptide: Transient receptor potential cation channel subfamily A member 1

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Supramolecule #1: transient receptor potential cation channel subfamily A member 1

SupramoleculeName: transient receptor potential cation channel subfamily A member 1
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
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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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: OTHER / 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: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6v9x

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.81 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 203880
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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