[English] 日本語
![](img/lk-miru.gif)
- PDB-8w2l: TRPM7 structure in complex with anticancer agent CCT128930 in clo... -
+
Open data
-
Basic information
Entry | Database: PDB / ID: 8w2l | ||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Title | TRPM7 structure in complex with anticancer agent CCT128930 in closed state | ||||||||||||||||||
![]() | Green fluorescent protein,Transient receptor potential cation channel subfamily M member 7 | ||||||||||||||||||
![]() | MEMBRANE PROTEIN / transient receptor potential M family member 7 / TRP / channel / TRPM7 / TRP channels / CCT128930 | ||||||||||||||||||
Function / homology | ![]() intracellular magnesium ion homeostasis / calcium-dependent cell-matrix adhesion / varicosity / TRP channels / actomyosin structure organization / myosin binding / monoatomic cation transmembrane transport / necroptotic process / monoatomic cation channel activity / ruffle ...intracellular magnesium ion homeostasis / calcium-dependent cell-matrix adhesion / varicosity / TRP channels / actomyosin structure organization / myosin binding / monoatomic cation transmembrane transport / necroptotic process / monoatomic cation channel activity / ruffle / bioluminescence / generation of precursor metabolites and energy / protein tetramerization / calcium channel activity / memory / synaptic vesicle membrane / calcium ion transport / kinase activity / actin binding / non-specific serine/threonine protein kinase / protein kinase activity / positive regulation of apoptotic process / phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / neuronal cell body / ATP binding / metal ion binding / plasma membrane Similarity search - Function | ||||||||||||||||||
Biological species | ![]() ![]() ![]() ![]() | ||||||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.45 Å | ||||||||||||||||||
![]() | Nadezhdin, K.D. / Sobolevsky, A.I. | ||||||||||||||||||
Funding support | ![]() ![]()
| ||||||||||||||||||
![]() | ![]() Title: Structural basis of selective TRPM7 inhibition by the anticancer agent CCT128930. Authors: Kirill D Nadezhdin / Leonor Correia / Alexey Shalygin / Muhammed Aktolun / Arthur Neuberger / Thomas Gudermann / Maria G Kurnikova / Vladimir Chubanov / Alexander I Sobolevsky / ![]() ![]() Abstract: TRP channels are implicated in various diseases, but high structural similarity between them makes selective pharmacological modulation challenging. Here, we study the molecular mechanism underlying ...TRP channels are implicated in various diseases, but high structural similarity between them makes selective pharmacological modulation challenging. Here, we study the molecular mechanism underlying specific inhibition of the TRPM7 channel, which is essential for cancer cell proliferation, by the anticancer agent CCT128930 (CCT). Using cryo-EM, functional analysis, and MD simulations, we show that CCT binds to a vanilloid-like (VL) site, stabilizing TRPM7 in the closed non-conducting state. Similar to other allosteric inhibitors of TRPM7, NS8593 and VER155008, binding of CCT is accompanied by displacement of a lipid that resides in the VL site in the apo condition. Moreover, we demonstrate the principal role of several residues in the VL site enabling CCT to inhibit TRPM7 without impacting the homologous TRPM6 channel. Hence, our results uncover the central role of the VL site for the selective interaction of TRPM7 with small molecules that can be explored in future drug design. | ||||||||||||||||||
History |
|
-
Structure visualization
Structure viewer | Molecule: ![]() ![]() |
---|
-
Downloads & links
-
Download
PDBx/mmCIF format | ![]() | 821.7 KB | Display | ![]() |
---|---|---|---|---|
PDB format | ![]() | 659 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 2.6 MB | Display | ![]() |
---|---|---|---|---|
Full document | ![]() | 2.6 MB | Display | |
Data in XML | ![]() | 138.7 KB | Display | |
Data in CIF | ![]() | 197.3 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 43751MC 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: 175756.250 Da / Num. of mol.: 4 / Fragment: residues 3-1280 of the TRPM7 channel Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() Gene: GFP, Trpm7, Chak, Ltrpc7 / Production host: ![]() References: UniProt: P42212, UniProt: Q923J1, non-specific serine/threonine protein kinase |
---|
-Non-polymers , 6 types, 229 molecules ![](data/chem/img/POV.gif)
![](data/chem/img/CLR.gif)
![](data/chem/img/M05.gif)
![](data/chem/img/DU0.gif)
![](data/chem/img/CA.gif)
![](data/chem/img/HOH.gif)
![](data/chem/img/CLR.gif)
![](data/chem/img/M05.gif)
![](data/chem/img/DU0.gif)
![](data/chem/img/CA.gif)
![](data/chem/img/HOH.gif)
#2: Chemical | ChemComp-POV / ( #3: Chemical | ChemComp-CLR / #4: Chemical | ChemComp-M05 / #5: Chemical | ChemComp-DU0 / #6: Chemical | ChemComp-CA / | #7: Water | ChemComp-HOH / | |
---|
-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: Complex of TRPM7 with antagonist CCT128930 / Type: COMPLEX / Entity ID: #1 / Source: MULTIPLE SOURCES | ||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Molecular weight | Value: 0.7 MDa / Experimental value: NO | ||||||||||||||||||||
Buffer solution | pH: 8 | ||||||||||||||||||||
Buffer component |
| ||||||||||||||||||||
Specimen | Conc.: 1.9 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||
Specimen support | Grid material: GOLD / Grid type: UltrAuFoil R1.2/1.3 | ||||||||||||||||||||
Vitrification | Cryogen name: ETHANE |
-
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: 1500 nm / Nominal defocus min: 750 nm |
Image recording | Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-
Processing
EM software |
| ||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 2.45 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 433041 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
|