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- PDB-6v9y: Structure of TRPA1 bound with A-967079, PMAL-C8 -

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Basic information

Entry
Database: PDB / ID: 6v9y
TitleStructure of TRPA1 bound with A-967079, PMAL-C8
ComponentsTransient receptor potential cation channel subfamily A member 1
KeywordsTRANSPORT PROTEIN / Membrane protein
Function / homology
Function and homology information


temperature-gated cation channel activity / stereocilium bundle / detection of chemical stimulus involved in sensory perception of pain / thermoception / TRP channels / channel activity / response to pain / cellular response to organic substance / intracellularly gated calcium channel activity / detection of mechanical stimulus involved in sensory perception of pain ...temperature-gated cation channel activity / stereocilium bundle / detection of chemical stimulus involved in sensory perception of pain / thermoception / TRP channels / channel activity / response to pain / cellular response to organic substance / intracellularly gated calcium channel activity / detection of mechanical stimulus involved in sensory perception of pain / monoatomic ion transport / sensory perception of pain / response to cold / response to organic substance / calcium ion transmembrane transport / calcium channel activity / intracellular calcium ion homeostasis / response to organic cyclic compound / cellular response to hydrogen peroxide / protein homotetramerization / cell surface receptor signaling pathway / response to xenobiotic stimulus / 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: 3.6 Å
AuthorsZhao, J. / Lin King, J.V. / Paulsen, C.E. / Cheng, Y. / Julius, D.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R35 NS105038 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM098672 United States
CitationJournal: Nature / Year: 2020
Title: Irritant-evoked activation and calcium modulation of the TRPA1 receptor.
Authors: Jianhua Zhao / John V Lin King / Candice E Paulsen / Yifan Cheng / David Julius /
Abstract: The transient receptor potential ion channel TRPA1 is expressed by primary afferent nerve fibres, in which it functions as a low-threshold sensor for structurally diverse electrophilic irritants, ...The transient receptor potential ion channel TRPA1 is expressed by primary afferent nerve fibres, in which it functions as a low-threshold sensor for structurally diverse electrophilic irritants, including small volatile environmental toxicants and endogenous algogenic lipids. TRPA1 is also a 'receptor-operated' channel whose activation downstream of metabotropic receptors elicits inflammatory pain or itch, making it an attractive target for novel analgesic therapies. However, the mechanisms by which TRPA1 recognizes and responds to electrophiles or cytoplasmic second messengers remain unknown. Here we use strutural studies and electrophysiology to show that electrophiles act through a two-step process in which modification of a highly reactive cysteine residue (C621) promotes reorientation of a cytoplasmic loop to enhance nucleophilicity and modification of a nearby cysteine (C665), thereby stabilizing the loop in an activating configuration. These actions modulate two restrictions controlling ion permeation, including widening of the selectivity filter to enhance calcium permeability and opening of a canonical gate at the cytoplasmic end of the pore. We propose a model to explain functional coupling between electrophile action and these control points. We also characterize a calcium-binding pocket that is highly conserved across TRP channel subtypes and accounts for all aspects of calcium-dependent TRPA1 regulation, including potentiation, desensitization and activation by metabotropic receptors. These findings provide a structural framework for understanding how a broad-spectrum irritant receptor is controlled by endogenous and exogenous agents that elicit or exacerbate pain and itch.
History
DepositionDec 16, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 6, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 8, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Jul 22, 2020Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.3Jul 29, 2020Group: Database references / Structure summary / Category: audit_author / citation_author / Item: _citation_author.identifier_ORCID
Revision 1.4Sep 16, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.5Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)510,5864
Polymers510,5864
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: homology
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area28520 Å2
ΔGint-253 kcal/mol
Surface area103100 Å2

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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 / Wasabi receptor


Mass: 127646.539 Da / Num. of mol.: 4 / Mutation: D966E
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

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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: TRPA1 bound with A-967079, solubilized in PMAL-C8 / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Strain: HEK293F
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: unspecified
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Tecnai Polara / Image courtesy: FEI Company
MicroscopyModel: FEI POLARA 300
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 40 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 30321 / Symmetry type: POINT

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