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- PDB-9m8s: Cryo-EM structure of the human TRPA1 ion channel in ligand-free state. -

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Basic information

Entry
Database: PDB / ID: 9m8s
TitleCryo-EM structure of the human TRPA1 ion channel in ligand-free state.
ComponentsTransient receptor potential cation channel subfamily A member 1
KeywordsMEMBRANE PROTEIN / TRANSPORT 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsKang, M.M. / Zhang, Y.M. / Ding, X.F. / Wang, L.J. / Sun, W.Y. / Jiang, H. / Chen, D. / Xu, J.F. / Pang, X.Y.
Funding support1items
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, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Oct 29, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Transient receptor potential cation channel subfamily A member 1
A: Transient receptor potential cation channel subfamily A member 1
C: Transient receptor potential cation channel subfamily A member 1
D: Transient receptor potential cation channel subfamily A member 1


Theoretical massNumber of molelcules
Total (without water)510,6424
Polymers510,6424
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Transient receptor potential cation channel subfamily A member 1 / Ankyrin-like with transmembrane domains protein 1 / Transformation-sensitive protein p120 / p120 / ...Ankyrin-like with transmembrane domains protein 1 / Transformation-sensitive protein p120 / p120 / Wasabi receptor


Mass: 127660.570 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TRPA1, ANKTM1 / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: O75762
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: transient receptor potential cation channel subfamily A member 1
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293F
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: OTHER / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.21.1_5286 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 148984 / Symmetry type: POINT

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