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- PDB-6wj5: Structure of human TRPA1 in complex with inhibitor GDC-0334 -

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Basic information

Entry
Database: PDB / ID: 6wj5
TitleStructure of human TRPA1 in complex with inhibitor GDC-0334
ComponentsTransient receptor potential cation channel subfamily A member 1
KeywordsMEMBRANE PROTEIN/Inhibitor / TRPA1 / channel / inhibitor / antagonist / MEMBRANE PROTEIN / MEMBRANE PROTEIN-Inhibitor 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-LXY / 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
AuthorsRohou, A. / Rouge, L. / Arthur, C.P. / Volgraf, M. / Chen, H.
CitationJournal: J Exp Med / Year: 2021
Title: A TRPA1 inhibitor suppresses neurogenic inflammation and airway contraction for asthma treatment.
Authors: Alessia Balestrini / Victory Joseph / Michelle Dourado / Rebecca M Reese / Shannon D Shields / Lionel Rougé / Daniel D Bravo / Tania Chernov-Rogan / Cary D Austin / Huifen Chen / Lan Wang / ...Authors: Alessia Balestrini / Victory Joseph / Michelle Dourado / Rebecca M Reese / Shannon D Shields / Lionel Rougé / Daniel D Bravo / Tania Chernov-Rogan / Cary D Austin / Huifen Chen / Lan Wang / Elisia Villemure / Daniel G M Shore / Vishal A Verma / Baihua Hu / Yong Chen / Laurie Leong / Chris Bjornson / Kathy Hötzel / Alvin Gogineni / Wyne P Lee / Eric Suto / Xiumin Wu / John Liu / Juan Zhang / Vineela Gandham / Jianyong Wang / Jian Payandeh / Claudio Ciferri / Alberto Estevez / Christopher P Arthur / Jens Kortmann / Ryan L Wong / Jose E Heredia / Jonas Doerr / Min Jung / Jason A Vander Heiden / Merone Roose-Girma / Lucinda Tam / Kai H Barck / Richard A D Carano / Han Ting Ding / Bobby Brillantes / Christine Tam / Xiaoying Yang / Simon S Gao / Justin Q Ly / Liling Liu / Liuxi Chen / Bianca M Liederer / Joseph H Lin / Steven Magnuson / Jun Chen / David H Hackos / Justin Elstrott / Alexis Rohou / Brian S Safina / Matthew Volgraf / Rebecca N Bauer / Lorena Riol-Blanco /
Abstract: Despite the development of effective therapies, a substantial proportion of asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential ...Despite the development of effective therapies, a substantial proportion of asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential cation channel member A1 (TRPA1) agonists are elevated in human asthmatic airways, and in rodents, TRPA1 is involved in the induction of airway inflammation and hyperreactivity. Here, the discovery and early clinical development of GDC-0334, a highly potent, selective, and orally bioavailable TRPA1 antagonist, is described. GDC-0334 inhibited TRPA1 function on airway smooth muscle and sensory neurons, decreasing edema, dermal blood flow (DBF), cough, and allergic airway inflammation in several preclinical species. In a healthy volunteer Phase 1 study, treatment with GDC-0334 reduced TRPA1 agonist-induced DBF, pain, and itch, demonstrating GDC-0334 target engagement in humans. These data provide therapeutic rationale for evaluating TRPA1 inhibition as a clinical therapy for asthma.
History
DepositionApr 11, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 17, 2021Provider: repository / Type: Initial release
Revision 1.1Aug 4, 2021Group: 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.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Aug 11, 2021Group: Database references / Category: database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)292,9268
Polymers290,4894
Non-polymers2,4384
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-LXY / (4R,5S)-4-fluoro-1-[(4-fluorophenyl)sulfonyl]-5-methyl-N-({5-(trifluoromethyl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl}methyl)-L-prolinamide


Mass: 609.492 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H19F8N5O3S / 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 inhibitor GDC-0334 / 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
41 mMIns6P1
SpecimenConc.: 0.33 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: Grid was gold-coated. Glow discharge using GloQube, negative polarity.
Grid material: COPPER / Grid type: C-flat-2/1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K / Details: 2 x 4s blot time

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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: 130000 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: 10 sec. / Electron dose: 47.5 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 QUANTUM (4k x 4k) / Num. of grids imaged: 1
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
IDNameCategory
2SerialEMimage acquisition
4cisTEMCTF correction
7Cootmodel fitting
8ISOLDEmodel fitting
10cisTEMinitial Euler assignment
11cisTEMfinal Euler assignment
12cisTEMclassification
13cisTEM3D reconstruction
14PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 4114800
Details: 15,630 movies were selected because of the quality of their CTF fits. 4,114,800 coordinates were selected, leading to 466,632 particles which clustered into high-quality 2D class averages
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 58836 / Algorithm: FOURIER SPACE
Details: Data at spatial frequencies higher than 1/4.8 A-1 were not used during any part of the refinement.
Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: AB INITIO MODEL / Space: REAL
Details: CCG MOE was used for refinement after Phenix real-space refinement.
Atomic model buildingPDB-ID: 3J9P

3j9p

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