[English] 日本語
![](img/lk-miru.gif)
- PDB-8foa: Cryo-EM structure of human TRPV6 in complex with the natural phyt... -
+
Open data
-
Basic information
Entry | Database: PDB / ID: 8foa | ||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Title | Cryo-EM structure of human TRPV6 in complex with the natural phytoestrogen genistein | ||||||||||||||||||
![]() | Transient receptor potential cation channel subfamily V member 6 | ||||||||||||||||||
![]() | MEMBRANE PROTEIN / transient receptor potential V family member 6 / TRP / human / channel / open / TRPV6 / inhibitor / blocker / antagonist / genistein / phytoestrogen / isoflavone / TRP channels / cancer / oncochannel / natural compound | ||||||||||||||||||
Function / homology | ![]() parathyroid hormone secretion / regulation of calcium ion-dependent exocytosis / TRP channels / calcium ion import across plasma membrane / calcium ion homeostasis / calcium channel complex / calcium ion transmembrane transport / calcium channel activity / response to calcium ion / calcium ion transport ...parathyroid hormone secretion / regulation of calcium ion-dependent exocytosis / TRP channels / calcium ion import across plasma membrane / calcium ion homeostasis / calcium channel complex / calcium ion transmembrane transport / calcium channel activity / response to calcium ion / calcium ion transport / calmodulin binding / identical protein binding / metal ion binding / plasma membrane Similarity search - Function | ||||||||||||||||||
Biological species | ![]() | ||||||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.66 Å | ||||||||||||||||||
![]() | Neuberger, A. / Yelshanskaya, M.V. / Nadezhdin, K.D. / Sobolevsky, A.I. | ||||||||||||||||||
Funding support | ![]() ![]()
| ||||||||||||||||||
![]() | ![]() Title: Structural mechanism of human oncochannel TRPV6 inhibition by the natural phytoestrogen genistein. Authors: Arthur Neuberger / Yury A Trofimov / Maria V Yelshanskaya / Kirill D Nadezhdin / Nikolay A Krylov / Roman G Efremov / Alexander I Sobolevsky / ![]() ![]() Abstract: Calcium-selective oncochannel TRPV6 is the major driver of cell proliferation in human cancers. While significant effort has been invested in the development of synthetic TRPV6 inhibitors, natural ...Calcium-selective oncochannel TRPV6 is the major driver of cell proliferation in human cancers. While significant effort has been invested in the development of synthetic TRPV6 inhibitors, natural channel blockers have been largely neglected. Here we report the structure of human TRPV6 in complex with the plant-derived phytoestrogen genistein, extracted from Styphnolobium japonicum, that was shown to inhibit cell invasion and metastasis in cancer clinical trials. Despite the pharmacological value, the molecular mechanism of TRPV6 inhibition by genistein has remained enigmatic. We use cryo-EM combined with electrophysiology, calcium imaging, mutagenesis, and molecular dynamics simulations to show that genistein binds in the intracellular half of the TRPV6 pore and acts as an ion channel blocker and gating modifier. Genistein binding to the open channel causes pore closure and a two-fold symmetrical conformational rearrangement in the S4-S5 and S6-TRP helix regions. The unprecedented mechanism of TRPV6 inhibition by genistein uncovers new possibilities in structure-based drug design. | ||||||||||||||||||
History |
|
-
Structure visualization
Structure viewer | Molecule: ![]() ![]() |
---|
-
Downloads & links
-
Download
PDBx/mmCIF format | ![]() | 471 KB | Display | ![]() |
---|---|---|---|---|
PDB format | ![]() | 391 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 2.7 MB | Display | ![]() |
---|---|---|---|---|
Full document | ![]() | 2.9 MB | Display | |
Data in XML | ![]() | 101.4 KB | Display | |
Data in CIF | ![]() | 133.8 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 29343MC ![]() 8fobC M: map data used to model this data C: citing same article ( |
---|---|
Similar structure data | Similarity search - Function & homology ![]() |
-
Links
-
Assembly
Deposited unit | ![]()
|
---|---|
1 |
|
-
Components
-Protein , 1 types, 4 molecules ABCD
#1: Protein | Mass: 83302.828 Da / Num. of mol.: 4 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
---|
-Non-polymers , 5 types, 53 molecules ![](data/chem/img/Y01.gif)
![](data/chem/img/POV.gif)
![](data/chem/img/ZN.gif)
![](data/chem/img/CA.gif)
![](data/chem/img/GEN.gif)
![](data/chem/img/POV.gif)
![](data/chem/img/ZN.gif)
![](data/chem/img/CA.gif)
![](data/chem/img/GEN.gif)
#2: Chemical | ChemComp-Y01 / #3: Chemical | ChemComp-POV / ( #4: Chemical | #5: Chemical | ChemComp-CA / | #6: Chemical | |
---|
-Details
Has ligand of interest | Y |
---|
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
---|---|
EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-
Sample preparation
Component | Name: sample 1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT | ||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Molecular weight | Value: 0.08322 MDa / Experimental value: NO | ||||||||||||||||||||||||||||||
Source (natural) | Organism: ![]() | ||||||||||||||||||||||||||||||
Source (recombinant) | Organism: ![]() | ||||||||||||||||||||||||||||||
Buffer solution | pH: 8 | ||||||||||||||||||||||||||||||
Buffer component |
| ||||||||||||||||||||||||||||||
Specimen | Conc.: 3.36 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: human TRPV6 | ||||||||||||||||||||||||||||||
Specimen support | Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3 | ||||||||||||||||||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K |
-
Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
---|---|
Microscopy | Model: TFS KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm |
Image recording | Average exposure time: 2.5 sec. / Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 3630 |
Image scans | Width: 5760 / Height: 4092 |
-
Processing
EM software |
| ||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
CTF correction | Type: NONE | ||||||||||||||||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 2343818 | ||||||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 2.66 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 196340 / Symmetry type: POINT | ||||||||||||||||||||||||||||||||||||||||
Atomic model building | Space: REAL | ||||||||||||||||||||||||||||||||||||||||
Atomic model building | PDB-ID: 7MIJ Accession code: 7MIJ / Source name: PDB / Type: experimental model | ||||||||||||||||||||||||||||||||||||||||
Refine LS restraints |
|