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- EMDB-26663: Tau Paired Helical Filament from Alzheimer's Disease not incubate... -

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Basic information

Entry
Database: EMDB / ID: EMD-26663
TitleTau Paired Helical Filament from Alzheimer's Disease not incubated with EGCG
Map data
Sample
  • Tissue: Tau Paired Helical Filament from Alzheimer's Disease not incubated with EGCG
    • Protein or peptide: Isoform Tau-F of Microtubule-associated protein tau
KeywordsAmyloid / fibril / Alzheimer's / disease / PROTEIN FIBRIL
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)
Methodhelical reconstruction / cryo EM / Resolution: 3.4 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-
UpdateJun 12, 2024-
Current statusJun 12, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26663.png

Downloads & links

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Map

FileDownload / File: emd_26663.map.gz / Format: CCP4 / Size: 15.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 160 pix.
= 172.48 Å		1.08 Å/pix.
x 160 pix.
= 172.48 Å		1.08 Å/pix.
x 160 pix.
= 172.48 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.078 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0118
Minimum - Maximum-0.028626695 - 0.05319137
Average (Standard dev.)0.0015111483 (±0.006089377)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-80-80-80
Dimensions160160160
Spacing160160160
CellA=B=C: 172.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_26663_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: #2

Fileemd_26663_half_map_2.map
Projections & Slices
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Sample components

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Entire : Tau Paired Helical Filament from Alzheimer's Disease not incubate...

EntireName: Tau Paired Helical Filament from Alzheimer's Disease not incubated with EGCG
Components
  • Tissue: Tau Paired Helical Filament from Alzheimer's Disease not incubated with EGCG
    • Protein or peptide: Isoform Tau-F of Microtubule-associated protein tau

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Supramolecule #1: Tau Paired Helical Filament from Alzheimer's Disease not incubate...

SupramoleculeName: Tau Paired Helical Filament from Alzheimer's Disease not incubated with EGCG
type: tissue / ID: 1 / Parent: 0 / Macromolecule list: all
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: Homo sapiens (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

UniProtKB: Isoform Tau-F of Microtubule-associated protein tau

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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
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number real images: 2651 / Average electron dose: 1.67 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 2.4 Å
Applied symmetry - Helical parameters - Δ&Phi: 179.47 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 33752
Startup modelType of model: OTHER
Details: Featureless gaussian cylinder generated from relion_helix_toolbox.
Final angle assignmentType: NOT APPLICABLE

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Atomic model buiding 1

Initial modelPDB ID:

6hre


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL
Output model

PDB-7upe:
Tau Paired Helical Filament from Alzheimer's Disease not incubated with EGCG

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