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- PDB-7jup: Structure of human TRPA1 in complex with antagonist compound 21 -

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Basic information

Entry
Database: PDB / ID: 7jup
TitleStructure of human TRPA1 in complex with antagonist compound 21
ComponentsTransient receptor potential cation channel subfamily A member 1
KeywordsMEMBRANE PROTEIN/Antagonist / TRPA1 / channel / agonist / MEMBRANE PROTEIN / MEMBRANE PROTEIN-Antagonist complex
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
Chem-VKM / Transient receptor potential cation channel subfamily A member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.05 Å
AuthorsRohou, A. / Rouge, L.
CitationJournal: J Med Chem / Year: 2021
Title: Tetrahydrofuran-Based Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonists: Ligand-Based Discovery, Activity in a Rodent Asthma Model, and Mechanism-of-Action via Cryogenic Electron Microscopy.
Authors: Jack A Terrett / Huifen Chen / Daniel G Shore / Elisia Villemure / Robin Larouche-Gauthier / Martin Déry / Francis Beaumier / Léa Constantineau-Forget / Chantal Grand-Maître / Luce ...Authors: Jack A Terrett / Huifen Chen / Daniel G Shore / Elisia Villemure / Robin Larouche-Gauthier / Martin Déry / Francis Beaumier / Léa Constantineau-Forget / Chantal Grand-Maître / Luce Lépissier / Stéphane Ciblat / Claudio Sturino / Yong Chen / Baihua Hu / Aijun Lu / Yunli Wang / Andrew P Cridland / Stuart I Ward / David H Hackos / Rebecca M Reese / Shannon D Shields / Jun Chen / Alessia Balestrini / Lorena Riol-Blanco / Wyne P Lee / John Liu / Eric Suto / Xiumin Wu / Juan Zhang / Justin Q Ly / Hank La / Kevin Johnson / Matt Baumgardner / Kang-Jye Chou / Alexis Rohou / Lionel Rougé / Brian S Safina / Steven Magnuson / Matthew Volgraf /
Abstract: Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium-permeable ion channel highly expressed in the primary sensory neurons functioning as a polymodal sensor for exogenous and ...Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium-permeable ion channel highly expressed in the primary sensory neurons functioning as a polymodal sensor for exogenous and endogenous stimuli and has generated widespread interest as a target for inhibition due to its implication in neuropathic pain and respiratory disease. Herein, we describe the optimization of a series of potent, selective, and orally bioavailable TRPA1 small molecule antagonists, leading to the discovery of a novel tetrahydrofuran-based linker. Given the balance of physicochemical properties and strong target engagement in a rat AITC-induced pain assay, compound was progressed into a guinea pig ovalbumin asthma model where it exhibited significant dose-dependent reduction of inflammatory response. Furthermore, the structure of the TRPA1 channel bound to compound was determined via cryogenic electron microscopy to a resolution of 3 Å, revealing the binding site and mechanism of action for this class of antagonists.
History
DepositionAug 20, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 31, 2021Provider: repository / Type: Initial release
Revision 1.1Apr 21, 2021Group: 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 1.2Mar 6, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_3d_fitting_list / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type

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Structure visualization

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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
C: Transient receptor potential cation channel subfamily A member 1
D: Transient receptor potential cation channel subfamily A member 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)292,0748
Polymers290,4894
Non-polymers1,5864
Water0
1


  • Idetical with deposited unit
  • defined by author
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 / Wasabi receptor


Mass: 72622.125 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TRPA1, ANKTM1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O75762
#2: Chemical
ChemComp-VKM / 1-({3-[(3R,5R)-5-(4-fluorophenyl)oxolan-3-yl]-1,2,4-oxadiazol-5-yl}methyl)-7-methyl-1,7-dihydro-6H-purin-6-one


Mass: 396.375 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H17FN6O3 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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 by antagonist compound 21 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightUnits: MEGADALTONS / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 8.2
Buffer component
IDConc.NameFormulaBuffer-ID
125 mMTris1
2150 mMNaClSodium chlorideNaClSodium chloride1
30.5 mMTCEP1
SpecimenConc.: 0.33 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: Solarus plasma cleaner / Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R2/2
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K
Details: Triple blot. Put blot in vitroblot Apply 3.5ul to grid, wait 30sec, blot manually Apply 3.5ul to grid, wait 30sec, blot manually, apply final 3.5ul, final blot by vitrobot (3.5s)

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 165000 X / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 1.6 sec. / Electron dose: 41.8 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 QUANTUM (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 8915
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV
Image scansSampling size: 5 µm / Movie frames/image: 40 / Used frames/image: 1-40

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Processing

EM software
IDNameVersionCategoryDetails
1cisTEM1particle selection
2SerialEMimage acquisition
4cisTEMCTF correction
7Cootmodel fitting
8ISOLDEmodel fitting
10cisTEMinitial Euler assignment
11cisTEMfinal Euler assignment
12cisTEMclassification3D reconstruction
13cisTEM3D reconstruction
14PHENIX3D reconstructiondensity modification
15PHENIXmodel refinement
16Cootmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 395169
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 3.05 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 101265 / Algorithm: FOURIER SPACE / Details: No data beyond 4.4 A were used during refinement. / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingPDB-ID: 6X2J

6x2j


Accession code: 6X2J / Source name: PDB / Type: experimental model

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