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- PDB-7upe: Tau Paired Helical Filament from Alzheimer's Disease not incubate... -

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Basic information

Entry
Database: PDB / ID: 7upe
TitleTau Paired Helical Filament from Alzheimer's Disease not incubated with EGCG
ComponentsIsoform Tau-F of Microtubule-associated protein tau
KeywordsPROTEIN FIBRIL / Amyloid / fibril / Alzheimer's / disease
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)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsSeidler, P.M. / Murray, K.A. / Boyer, D.R. / Ge, P. / Sawaya, M.R. / Eisenberg, D.S.
Funding support United States, 4items
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, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 28, 2022Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isoform Tau-F of Microtubule-associated protein tau
B: Isoform Tau-F of Microtubule-associated protein tau
C: Isoform Tau-F of Microtubule-associated protein tau
D: Isoform Tau-F of Microtubule-associated protein tau
E: Isoform Tau-F of Microtubule-associated protein tau
F: Isoform Tau-F of Microtubule-associated protein tau
G: Isoform Tau-F of Microtubule-associated protein tau
H: Isoform Tau-F of Microtubule-associated protein tau
I: Isoform Tau-F of Microtubule-associated protein tau
J: Isoform Tau-F of Microtubule-associated protein tau


Theoretical massNumber of molelcules
Total (without water)459,19910
Polymers459,19910
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Isoform Tau-F of Microtubule-associated protein tau / Neurofibrillary tangle protein / Paired helical filament-tau / PHF-tau


Mass: 45919.871 Da / Num. of mol.: 10 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P10636-8

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: HELICAL ARRAY / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: Tau Paired Helical Filament from Alzheimer's Disease not incubated with EGCG
Type: TISSUE / Entity ID: all / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 1.67 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of real images: 2651

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
EM software
IDNameCategory
7Cootmodel fitting
12RELION3D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 179.47 ° / Axial rise/subunit: 2.4 Å / Axial symmetry: C1
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 33752 / Symmetry type: HELICAL
Atomic model buildingSpace: REAL
Atomic model buildingPDB-ID: 6HRE

6hre

Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0045860
ELECTRON MICROSCOPYf_angle_d0.7277840
ELECTRON MICROSCOPYf_dihedral_angle_d6.231770
ELECTRON MICROSCOPYf_chiral_restr0.058880
ELECTRON MICROSCOPYf_plane_restr0.0091000

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