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- EMDB-29458: Alzheimer's disease paired-helical filament in complex with PET t... -

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Basic information

Entry
Database: EMDB / ID: EMD-29458
TitleAlzheimer's disease paired-helical filament in complex with PET tracer GTP-1
Map data
Sample
  • Complex: Alzheimer's tau paired helical filament in complex with PET ligand GTP-1
    • Protein or peptide: Microtubule-associated protein tau
  • Ligand: (5S)-2-[4-(2-fluoroethyl)piperidin-1-yl]pyrimido[1,2-a]benzimidazole
KeywordsNeurodegeneration / Positron Emission Tomography / Filament / Alzheimer's disease / PROTEIN FIBRIL
Function / homology
Function and homology information


plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / negative regulation of protein localization to mitochondrion / neurofibrillary tangle / microtubule lateral binding / axonal transport / tubulin complex / positive regulation of protein localization to synapse / phosphatidylinositol bisphosphate binding / generation of neurons ...plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / negative regulation of protein localization to mitochondrion / neurofibrillary tangle / microtubule lateral binding / axonal transport / tubulin complex / positive regulation of protein localization to synapse / phosphatidylinositol bisphosphate binding / generation of neurons / rRNA metabolic process / axonal transport of mitochondrion / regulation of mitochondrial fission / axon development / regulation of microtubule-based movement / regulation of chromosome organization / intracellular distribution of mitochondria / central nervous system neuron development / minor groove of adenine-thymine-rich DNA binding / lipoprotein particle binding / microtubule polymerization / negative regulation of mitochondrial membrane potential / regulation of microtubule polymerization / dynactin binding / apolipoprotein binding / protein polymerization / main axon / axolemma / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / negative regulation of mitochondrial fission / glial cell projection / neurofibrillary tangle assembly / positive regulation of axon extension / positive regulation of microtubule polymerization / regulation of cellular response to heat / Activation of AMPK downstream of NMDARs / positive regulation of protein localization / positive regulation of superoxide anion generation / supramolecular fiber organization / cellular response to brain-derived neurotrophic factor stimulus / regulation of long-term synaptic depression / cytoplasmic microtubule organization / regulation of calcium-mediated signaling / somatodendritic compartment / axon cytoplasm / synapse assembly / astrocyte activation / phosphatidylinositol binding / nuclear periphery / enzyme inhibitor activity / protein phosphatase 2A binding / stress granule assembly / regulation of microtubule cytoskeleton organization / regulation of autophagy / cellular response to reactive oxygen species / microglial cell activation / cellular response to nerve growth factor stimulus / Hsp90 protein binding / protein homooligomerization / PKR-mediated signaling / SH3 domain binding / regulation of synaptic plasticity / synapse organization / response to lead ion / microtubule cytoskeleton organization / memory / cytoplasmic ribonucleoprotein granule / neuron projection development / cell-cell signaling / single-stranded DNA binding / cellular response to heat / growth cone / protein-folding chaperone binding / microtubule cytoskeleton / actin binding / cell body / double-stranded DNA binding / microtubule binding / sequence-specific DNA binding / amyloid fibril formation / dendritic spine / microtubule / protein-macromolecule adaptor activity / learning or memory / neuron projection / membrane raft / negative regulation of gene expression / axon / neuronal cell body / DNA damage response / dendrite / protein kinase binding / enzyme binding / mitochondrion / DNA binding / RNA binding / extracellular region / identical protein binding / nucleus
Similarity search - Function
Microtubule-associated protein Tau / Microtubule associated protein, tubulin-binding repeat / Tau and MAP protein, tubulin-binding repeat / Tau and MAP proteins tubulin-binding repeat signature. / Tau and MAP proteins tubulin-binding repeat profile. / :
Similarity search - Domain/homology
Microtubule-associated protein tau
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsMerz GE / Tse E / Southworth DR
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)AG002132 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM139379 United States
CitationJournal: Nat Commun / Year: 2023
Title: Stacked binding of a PET ligand to Alzheimer's tau paired helical filaments.
Authors: Gregory E Merz / Matthew J Chalkley / Sophia K Tan / Eric Tse / Joanne Lee / Stanley B Prusiner / Nick A Paras / William F DeGrado / Daniel R Southworth /
Abstract: Accumulation of filamentous aggregates of tau protein in the brain is a pathological hallmark of Alzheimer's disease (AD) and many other neurodegenerative tauopathies. The filaments adopt disease- ...Accumulation of filamentous aggregates of tau protein in the brain is a pathological hallmark of Alzheimer's disease (AD) and many other neurodegenerative tauopathies. The filaments adopt disease-specific cross-β amyloid conformations that self-propagate and are implicated in neuronal loss. Development of molecular diagnostics and therapeutics is of critical importance. However, mechanisms of small molecule binding to the amyloid core is poorly understood. We used cryo-electron microscopy to determine a 2.7 Å structure of AD patient-derived tau paired-helical filaments bound to the PET ligand GTP-1. The compound is bound stoichiometrically at a single site along an exposed cleft of each protofilament in a stacked arrangement matching the fibril symmetry. Multiscale modeling reveals pi-pi aromatic interactions that pair favorably with the small molecule-protein contacts, supporting high specificity and affinity for the AD tau conformation. This binding mode offers critical insight into designing compounds to target different amyloid folds found across neurodegenerative diseases.
History
DepositionJan 17, 2023-
Header (metadata) releaseJun 7, 2023-
Map releaseJun 7, 2023-
UpdateJun 19, 2024-
Current statusJun 19, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29458.png

Downloads & links

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Map

FileDownload / File: emd_29458.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 288 pix.
= 240.192 Å		0.83 Å/pix.
x 288 pix.
= 240.192 Å		0.83 Å/pix.
x 288 pix.
= 240.192 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.834 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0163
Minimum - Maximum-0.048219703 - 0.09874879
Average (Standard dev.)0.00014452508 (±0.002731626)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 240.192 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_29458_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_29458_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Alzheimer's tau paired helical filament in complex with PET ligan...

EntireName: Alzheimer's tau paired helical filament in complex with PET ligand GTP-1
Components
  • Complex: Alzheimer's tau paired helical filament in complex with PET ligand GTP-1
    • Protein or peptide: Microtubule-associated protein tau
  • Ligand: (5S)-2-[4-(2-fluoroethyl)piperidin-1-yl]pyrimido[1,2-a]benzimidazole

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Supramolecule #1: Alzheimer's tau paired helical filament in complex with PET ligan...

SupramoleculeName: Alzheimer's tau paired helical filament in complex with PET ligand GTP-1
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Microtubule-associated protein tau

MacromoleculeName: Microtubule-associated protein tau / type: protein_or_peptide / ID: 1 / Number of copies: 23 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.940141 KDa
SequenceString:
VQIVYKPVDL SKVTSKCGSL GNIHHKPGGG QVEVKSEKLD FKDRVQSKIG SLDNITHVPG GGNKKIETHK LTF

UniProtKB: Microtubule-associated protein tau

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Macromolecule #2: (5S)-2-[4-(2-fluoroethyl)piperidin-1-yl]pyrimido[1,2-a]benzimidazole

MacromoleculeName: (5S)-2-[4-(2-fluoroethyl)piperidin-1-yl]pyrimido[1,2-a]benzimidazole
type: ligand / ID: 2 / Number of copies: 23 / Formula: Y9H
Molecular weightTheoretical: 298.358 Da
Chemical component information

ChemComp-Y9H:
(5S)-2-[4-(2-fluoroethyl)piperidin-1-yl]pyrimido[1,2-a]benzimidazole

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 7.4
Component:
ConcentrationNameFormula
20.0 mMTris-HCl
100.0 mMSodium ChlorideNaCl

Details: 20 mM Tris-HCl, pH 7.4, 100 mM NaCl
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 120 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number real images: 15160 / Average electron dose: 46.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 2.37 Å
Applied symmetry - Helical parameters - Δ&Phi: 179.45 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 30199
Segment selectionNumber selected: 380428 / Software - Name: RELION (ver. 3.1)
Startup modelType of model: EMDB MAP
EMDB ID:

0259

Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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