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- PDB-7rau: Structure of TRPV3 in complex with osthole -

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Basic information

Entry
Database: PDB / ID: 7rau
TitleStructure of TRPV3 in complex with osthole
ComponentsTransient receptor potential cation channel subfamily V member 3
KeywordsMEMBRANE PROTEIN / TRP channel / V3
Function / homology
Function and homology information


negative regulation of hair cycle / TRP channels / response to temperature stimulus / positive regulation of calcium ion import / monoatomic cation channel activity / calcium channel activity / monoatomic ion channel activity / receptor complex / membrane / identical protein binding
Similarity search - Function
Transient receptor potential cation channel subfamily V member 1-4 / Transient receptor potential cation channel subfamily V / 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
7-methoxy-8-(3-methylbut-2-enyl)chromen-2-one / Transient receptor potential cation channel subfamily V member 3
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.99 Å
AuthorsNeuberger, A. / Nadezhdin, K.D. / Sobolevsky, A.I.
Funding support United States, Germany, 5items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01 CA206573 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01 NS083660 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01 NS107253 United States
National Science Foundation (NSF, United States)1818086 United States
German Research Foundation (DFG)464295817 Germany
CitationJournal: EMBO Rep / Year: 2021
Title: Structural mechanism of TRPV3 channel inhibition by the plant-derived coumarin osthole.
Authors: Arthur Neuberger / Kirill D Nadezhdin / Eleonora Zakharian / Alexander I Sobolevsky /
Abstract: TRPV3, a representative of the vanilloid subfamily of TRP channels, is predominantly expressed in skin keratinocytes and has been implicated in cutaneous sensation and associated with numerous skin ...TRPV3, a representative of the vanilloid subfamily of TRP channels, is predominantly expressed in skin keratinocytes and has been implicated in cutaneous sensation and associated with numerous skin pathologies and cancers. TRPV3 is inhibited by the natural coumarin derivative osthole, an active ingredient of Cnidium monnieri, which has been used in traditional Chinese medicine for the treatment of a variety of human diseases. However, the structural basis of channel inhibition by osthole has remained elusive. Here we present cryo-EM structures of TRPV3 in complex with osthole, revealing two types of osthole binding sites in the transmembrane region of TRPV3 that coincide with the binding sites of agonist 2-APB. Osthole binding converts the channel pore into a previously unidentified conformation with a widely open selectivity filter and closed intracellular gate. Our structures provide insight into competitive inhibition of TRPV3 by osthole and can serve as a template for the design of osthole chemistry-inspired drugs targeting TRPV3-associated diseases.
History
DepositionJul 2, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 8, 2021Provider: repository / Type: Initial release
Revision 1.1Sep 15, 2021Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Nov 17, 2021Group: Database references / Category: citation / Item: _citation.journal_volume

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Structure visualization

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Assembly

Deposited unit
A: Transient receptor potential cation channel subfamily V member 3
B: Transient receptor potential cation channel subfamily V member 3
C: Transient receptor potential cation channel subfamily V member 3
D: Transient receptor potential cation channel subfamily V member 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)371,88012
Polymers369,9264
Non-polymers1,9548
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area16810 Å2
ΔGint-137 kcal/mol
Surface area126690 Å2

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Components

#1: Protein
Transient receptor potential cation channel subfamily V member 3 / TrpV3


Mass: 92481.547 Da / Num. of mol.: 4 / Mutation: Y564A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Trpv3 / Plasmid: pEG BacMam / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q8K424
#2: Chemical
ChemComp-A0O / 7-methoxy-8-(3-methylbut-2-enyl)chromen-2-one / Osthol


Mass: 244.286 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C15H16O3 / 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: sample 1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightUnits: MEGADALTONS / Experimental value: NO
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaClSodium chloride1
220 mMtris(hydroxymethyl)aminomethane1
30.01 %glyco-diosgenin (GDN)1
41 mMbeta-Mercaptoethanol2-Mercaptoethanol1
5400 uMosthole1
640 2-APB1
SpecimenConc.: 3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 200 divisions/in. / Grid type: C-flat-1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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 / Nominal defocus max: -3500 nm / Nominal defocus min: -1500 nm / Cs: 2.7 mm
Image recordingAverage exposure time: 4 sec. / Electron dose: 96.5 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 3997
Image scansWidth: 5760 / Height: 4092

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Processing

EM software
IDNameVersionCategory
1cryoSPARC2.14particle selection
2Leginonimage acquisition
4cryoSPARC2.14CTF correction
7Cootmodel fitting
9PHENIXmodel refinement
10cryoSPARC2.14initial Euler assignment
11cryoSPARC2.14final Euler assignment
12cryoSPARC2.14classification
13cryoSPARC2.143D reconstruction
CTF correctionType: NONE
Particle selectionNum. of particles selected: 1147004
3D reconstructionResolution: 3.99 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 63523 / Symmetry type: POINT
Atomic model buildingSpace: REAL

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