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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 / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / axonal transport / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / positive regulation of protein localization to synapse / microtubule lateral binding / tubulin complex ...plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / axonal transport / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / positive regulation of protein localization to synapse / microtubule lateral binding / tubulin complex / phosphatidylinositol bisphosphate binding / main axon / negative regulation of kinase activity / regulation of long-term synaptic depression / negative regulation of tubulin deacetylation / generation of neurons / rRNA metabolic process / internal protein amino acid acetylation / regulation of chromosome organization / regulation of mitochondrial fission / axonal transport of mitochondrion / intracellular distribution of mitochondria / axon development / central nervous system neuron development / regulation of microtubule polymerization / apolipoprotein binding / microtubule polymerization / lipoprotein particle binding / minor groove of adenine-thymine-rich DNA binding / dynactin binding / negative regulation of mitochondrial membrane potential / glial cell projection / protein polymerization / axolemma / negative regulation of mitochondrial fission / regulation of microtubule polymerization or depolymerization / Caspase-mediated cleavage of cytoskeletal proteins / positive regulation of axon extension / regulation of microtubule cytoskeleton organization / Activation of AMPK downstream of NMDARs / regulation of cellular response to heat / positive regulation of protein localization / cytoplasmic microtubule organization / stress granule assembly / supramolecular fiber organization / regulation of calcium-mediated signaling / axon cytoplasm / somatodendritic compartment / positive regulation of microtubule polymerization / synapse assembly / cellular response to brain-derived neurotrophic factor stimulus / nuclear periphery / phosphatidylinositol binding / cellular response to nerve growth factor stimulus / positive regulation of superoxide anion generation / protein phosphatase 2A binding / regulation of autophagy / astrocyte activation / response to lead ion / microglial cell activation / synapse organization / Hsp90 protein binding / protein homooligomerization / PKR-mediated signaling / regulation of synaptic plasticity / : / memory / SH3 domain binding / microtubule cytoskeleton organization / cytoplasmic ribonucleoprotein granule / cellular response to reactive oxygen species / microtubule cytoskeleton / neuron projection development / cell-cell signaling / protein-folding chaperone binding / single-stranded DNA binding / actin binding / cellular response to heat / protein-macromolecule adaptor activity / double-stranded DNA binding / growth cone / cell body / microtubule binding / sequence-specific DNA binding / microtubule / amyloid fibril formation / dendritic spine / learning or memory / nuclear speck / neuron projection / membrane raft / axon / negative regulation of gene expression / neuronal cell body / DNA damage response / dendrite / protein kinase binding / enzyme binding / mitochondrion / DNA binding
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

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_29458_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

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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