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- EMDB-29458: Alzheimer's disease paired-helical filament in complex with PET t... -
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Open data
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Basic information
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Title | Alzheimer's disease paired-helical filament in complex with PET tracer GTP-1 | |||||||||
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![]() | Neurodegeneration / Positron Emission Tomography / Filament / Alzheimer's disease / PROTEIN FIBRIL | |||||||||
Function / homology | ![]() 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 / regulation of long-term synaptic depression / negative regulation of kinase activity / negative regulation of tubulin deacetylation / generation of neurons / positive regulation of protein localization / 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 / microtubule polymerization / minor groove of adenine-thymine-rich DNA binding / lipoprotein particle binding / dynactin binding / glial cell projection / apolipoprotein binding / negative regulation of mitochondrial membrane potential / protein polymerization / axolemma / negative regulation of mitochondrial fission / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / positive regulation of axon extension / regulation of microtubule cytoskeleton organization / Activation of AMPK downstream of NMDARs / cytoplasmic microtubule organization / supramolecular fiber organization / regulation of cellular response to heat / stress granule assembly / regulation of calcium-mediated signaling / axon cytoplasm / positive regulation of microtubule polymerization / somatodendritic compartment / synapse assembly / cellular response to brain-derived neurotrophic factor stimulus / phosphatidylinositol binding / nuclear periphery / 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 / synapse organization / microglial cell activation / Hsp90 protein binding / PKR-mediated signaling / protein homooligomerization / regulation of synaptic plasticity / memory / microtubule cytoskeleton organization / SH3 domain binding / cellular response to reactive oxygen species / cytoplasmic ribonucleoprotein granule / activation of cysteine-type endopeptidase activity involved in apoptotic process / microtubule cytoskeleton / neuron projection development / cell-cell signaling / protein-macromolecule adaptor activity / single-stranded DNA binding / actin binding / protein-folding chaperone binding / cellular response to heat / cell body / growth cone / microtubule binding / double-stranded DNA binding / sequence-specific DNA binding / amyloid fibril formation / microtubule / dendritic spine / learning or memory / nuclear speck / neuron projection / membrane raft / axon / negative regulation of gene expression / neuronal cell body / dendrite / DNA damage response / protein kinase binding / enzyme binding / mitochondrion / DNA binding Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | helical reconstruction / cryo EM / Resolution: 2.7 Å | |||||||||
![]() | Merz GE / Tse E / Southworth DR | |||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 7.2 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 16.3 KB 16.3 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 10.2 KB | Display | ![]() |
Images | ![]() | 70.2 KB | ||
Filedesc metadata | ![]() | 5.6 KB | ||
Others | ![]() ![]() | 71.3 MB 71.3 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8fugMC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 0.834 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #1
File | emd_29458_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_29458_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
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Sample components
-Entire : Alzheimer's tau paired helical filament in complex with PET ligan...
Entire | Name: Alzheimer's tau paired helical filament in complex with PET ligand GTP-1 |
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Components |
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-Supramolecule #1: Alzheimer's tau paired helical filament in complex with PET ligan...
Supramolecule | Name: Alzheimer's tau paired helical filament in complex with PET ligand GTP-1 type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: Microtubule-associated protein tau
Macromolecule | Name: Microtubule-associated protein tau / type: protein_or_peptide / ID: 1 / Number of copies: 23 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 7.940141 KDa |
Sequence | String: VQIVYKPVDL SKVTSKCGSL GNIHHKPGGG QVEVKSEKLD FKDRVQSKIG SLDNITHVPG GGNKKIETHK LTF UniProtKB: Microtubule-associated protein tau |
-Macromolecule #2: (5S)-2-[4-(2-fluoroethyl)piperidin-1-yl]pyrimido[1,2-a]benzimidazole
Macromolecule | Name: (5S)-2-[4-(2-fluoroethyl)piperidin-1-yl]pyrimido[1,2-a]benzimidazole type: ligand / ID: 2 / Number of copies: 23 / Formula: Y9H |
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Molecular weight | Theoretical: 298.358 Da |
Chemical component information | ![]() ChemComp-Y9H: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | helical reconstruction |
Aggregation state | filament |
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Sample preparation
Buffer | pH: 7.4 Component:
Details: 20 mM Tris-HCl, pH 7.4, 100 mM NaCl | |||||||||
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Grid | Model: 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. | |||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Specialist optics | Energy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Number real images: 15160 / Average electron dose: 46.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination 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 |