[English] 日本語
![](img/lk-miru.gif)
- PDB-7upg: Tau Paired Helical Filament from Alzheimer's Disease incubated wi... -
+
Open data
-
Basic information
Entry | Database: PDB / ID: 7upg | |||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Title | Tau Paired Helical Filament from Alzheimer's Disease incubated with EGCG for 3 hours | |||||||||||||||
![]() | Isoform Tau-F of Microtubule-associated protein tau | |||||||||||||||
![]() | PROTEIN FIBRIL / Amyloid / fibril / Alzheimer's / disease / disaggregant | |||||||||||||||
Function / homology | Activation of AMPK downstream of NMDARs / PKR-mediated signaling / Chem-KDH / Isoform Tau-F of Microtubule-associated protein tau![]() | |||||||||||||||
Biological species | ![]() | |||||||||||||||
Method | ELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.8 Å | |||||||||||||||
![]() | Seidler, P.M. / Murray, K.A. / Boyer, D.R. / Ge, P. / Sawaya, M.R. / Eisenberg, D.S. | |||||||||||||||
Funding support | ![]()
| |||||||||||||||
![]() | ![]() Title: Structure-based discovery of small molecules that disaggregate Alzheimer's disease tissue derived tau fibrils in vitro. Authors: Paul M Seidler / Kevin A Murray / David R Boyer / Peng Ge / Michael R Sawaya / Carolyn J Hu / Xinyi Cheng / Romany Abskharon / Hope Pan / Michael A DeTure / Christopher K Williams / Dennis W ...Authors: Paul M Seidler / Kevin A Murray / David R Boyer / Peng Ge / Michael R Sawaya / Carolyn J Hu / Xinyi Cheng / Romany Abskharon / Hope Pan / Michael A DeTure / Christopher K Williams / Dennis W Dickson / Harry V Vinters / David S Eisenberg / ![]() Abstract: Alzheimer's disease (AD) is the consequence of neuronal death and brain atrophy associated with the aggregation of protein tau into fibrils. Thus disaggregation of tau fibrils could be a therapeutic ...Alzheimer's disease (AD) is the consequence of neuronal death and brain atrophy associated with the aggregation of protein tau into fibrils. Thus disaggregation of tau fibrils could be a therapeutic approach to AD. The small molecule EGCG, abundant in green tea, has long been known to disaggregate tau and other amyloid fibrils, but EGCG has poor drug-like properties, failing to fully penetrate the brain. Here we have cryogenically trapped an intermediate of brain-extracted tau fibrils on the kinetic pathway to EGCG-induced disaggregation and have determined its cryoEM structure. The structure reveals that EGCG molecules stack in polar clefts between the paired helical protofilaments that pathologically define AD. Treating the EGCG binding position as a pharmacophore, we computationally screened thousands of drug-like compounds for compatibility for the pharmacophore, discovering several that experimentally disaggregate brain-derived tau fibrils in vitro. This work suggests the potential of structure-based, small-molecule drug discovery for amyloid diseases. | |||||||||||||||
History |
|
-
Structure visualization
Structure viewer | Molecule: ![]() ![]() |
---|
-
Downloads & links
-
Download
PDBx/mmCIF format | ![]() | 187.3 KB | Display | ![]() |
---|---|---|---|---|
PDB format | ![]() | 126.3 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
---|
-Related structure data
Related structure data | ![]() 26665MC ![]() 7upeC ![]() 7upfC C: citing same article ( M: map data used to model this data |
---|---|
Similar structure data | Similarity search - Function & homology ![]() |
-
Links
-
Assembly
Deposited unit | ![]()
|
---|---|
1 |
|
-
Components
#1: Protein | Mass: 45919.871 Da / Num. of mol.: 10 / Source method: isolated from a natural source / Source: (natural) ![]() #2: Chemical | ChemComp-KDH / ( Has ligand of interest | Y | |
---|
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
---|---|
EM experiment | Aggregation state: HELICAL ARRAY / 3D reconstruction method: helical reconstruction |
-
Sample preparation
Component | Name: Tau Paired Helical Filament from Alzheimer's Disease incubated with EGCG for 3 hours Type: TISSUE / Entity ID: #1 / Source: NATURAL |
---|---|
Source (natural) | Organism: ![]() |
Buffer solution | pH: 7 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-
Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
---|---|
Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm |
Image recording | Electron dose: 0.66 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of real images: 6988 |
-
Processing
Software | Name: PHENIX / Version: 1.20_4459: / Classification: refinement | ||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
EM software |
| ||||||||||||||||||||||||
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
Helical symmerty | Angular rotation/subunit: 179.46 ° / Axial rise/subunit: 2.4 Å / Axial symmetry: C1 | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 29145 / Symmetry type: HELICAL | ||||||||||||||||||||||||
Atomic model building | Space: REAL | ||||||||||||||||||||||||
Atomic model building | PDB-ID: 6HRE Accession code: 6HRE / Source name: PDB / Type: experimental model | ||||||||||||||||||||||||
Refine LS restraints |
|