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- EMDB-26665: Tau Paired Helical Filament from Alzheimer's Disease incubated wi... -

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Entry
Database: EMDB / ID: EMD-26665
TitleTau Paired Helical Filament from Alzheimer's Disease incubated with EGCG for 3 hours
Map data
Sample
  • Tissue: Tau Paired Helical Filament from Alzheimer's Disease incubated with EGCG for 3 hours
    • Protein or peptide: Isoform Tau-F of Microtubule-associated protein tau
  • Ligand: (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromen-3-yl 3,4,5-trihydroxybenzoate
Function / homologyActivation of AMPK downstream of NMDARs / PKR-mediated signaling / Isoform Tau-F of Microtubule-associated protein tau
Function and homology information
Biological speciesHomo sapiens (human) / human (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsSeidler PM / Murray KA / Boyer DR / Ge P / Sawaya MR / Eisenberg DS
Funding support United States, 4 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)1R01 AG029430 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)AG061847 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)RF1 AG054022 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)1F32 NS095661 United States
CitationJournal: Nat Commun / Year: 2022
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
DepositionApr 15, 2022-
Header (metadata) releaseSep 28, 2022-
Map releaseSep 28, 2022-
UpdateSep 28, 2022-
Current statusSep 28, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26665.png

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Map

FileDownload / File: emd_26665.map.gz / Format: CCP4 / Size: 38.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.064 Å
Density
Contour LevelBy AUTHOR: 0.005
Minimum - Maximum-0.015728982 - 0.0270816
Average (Standard dev.)0.00043649913 (±0.002236967)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-108-108-108
Dimensions216216216
Spacing216216216
CellA=B=C: 229.824 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_26665_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_26665_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram (log scale)

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Sample components

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Entire : Tau Paired Helical Filament from Alzheimer's Disease incubated wi...

EntireName: Tau Paired Helical Filament from Alzheimer's Disease incubated with EGCG for 3 hours
Components
  • Tissue: Tau Paired Helical Filament from Alzheimer's Disease incubated with EGCG for 3 hours
    • Protein or peptide: Isoform Tau-F of Microtubule-associated protein tau
  • Ligand: (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromen-3-yl 3,4,5-trihydroxybenzoate

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Supramolecule #1: Tau Paired Helical Filament from Alzheimer's Disease incubated wi...

SupramoleculeName: Tau Paired Helical Filament from Alzheimer's Disease incubated with EGCG for 3 hours
type: tissue / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Isoform Tau-F of Microtubule-associated protein tau

MacromoleculeName: Isoform Tau-F of Microtubule-associated protein tau / type: protein_or_peptide / ID: 1 / Number of copies: 10 / Enantiomer: LEVO
Source (natural)Organism: human (human)
Molecular weightTheoretical: 45.919871 KDa
SequenceString: MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKESPLQT PTEDGSEEPG SETSDAKSTP TAEDVTAPLV DEGAPGKQA AAQPHTEIPE GTTAEEAGIG DTPSLEDEAA GHVTQARMVS KSKDGTGSDD KKAKGADGKT KIATPRGAAP P GQKGQANA ...String:
MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKESPLQT PTEDGSEEPG SETSDAKSTP TAEDVTAPLV DEGAPGKQA AAQPHTEIPE GTTAEEAGIG DTPSLEDEAA GHVTQARMVS KSKDGTGSDD KKAKGADGKT KIATPRGAAP P GQKGQANA TRIPAKTPPA PKTPPSSGEP PKSGDRSGYS SPGSPGTPGS RSRTPSLPTP PTREPKKVAV VRTPPKSPSS AK SRLQTAP VPMPDLKNVK SKIGSTENLK HQPGGGKVQI INKKLDLSNV QSKCGSKDNI KHVPGGGSVQ IVYKPVDLSK VTS KCGSLG NIHHKPGGGQ VEVKSEKLDF KDRVQSKIGS LDNITHVPGG GNKKIETHKL TFRENAKAKT DHGAEIVYKS PVVS GDTSP RHLSNVSSTG SIDMVDSPQL ATLADEVSAS LAKQGL

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Macromolecule #2: (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-c...

MacromoleculeName: (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromen-3-yl 3,4,5-trihydroxybenzoate
type: ligand / ID: 2 / Number of copies: 10 / Formula: KDH
Molecular weightTheoretical: 458.372 Da
Chemical component information

ChemComp-EGG:
(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromen-3-yl 3,4,5-trihydroxybenzoate / Epigallocatechin gallate

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statehelical array

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Sample preparation

BufferpH: 7
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Number real images: 6988 / Average electron dose: 0.66 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Details: Featureless gaussian cylinder generated from relion_helix_toolbox.
Final angle assignmentType: NOT APPLICABLE
Final reconstructionApplied symmetry - Helical parameters - Δz: 2.4 Å
Applied symmetry - Helical parameters - Δ&Phi: 179.46 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 29145

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Atomic model buiding 1

Initial modelPDB ID:

6hre

RefinementSpace: REAL
Output model

PDB-7upg:
Tau Paired Helical Filament from Alzheimer's Disease incubated with EGCG for 3 hours

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