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- EMDB-42463: Alzheimer's disease PHF complexed with PET ligand MK-6240 -

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Basic information

Entry
Database: EMDB / ID: EMD-42463
TitleAlzheimer's disease PHF complexed with PET ligand MK-6240
Map data
Sample
  • Tissue: Microtubule-associated protein tau
    • Protein or peptide: Microtubule-associated protein tau
  • Ligand: 6-fluoro-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine
KeywordsMK-6240 PET Ligand / AD PHF / PROTEIN FIBRIL
Function / homology
Function and homology information


plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / neurofibrillary tangle assembly / : / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / positive regulation of protein localization to synapse / microtubule lateral binding / axonal transport / main axon ...plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / neurofibrillary tangle assembly / : / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / positive regulation of protein localization to synapse / microtubule lateral binding / axonal transport / main axon / tubulin complex / regulation of long-term synaptic depression / phosphatidylinositol bisphosphate binding / negative regulation of tubulin deacetylation / negative regulation of kinase activity / generation of neurons / internal protein amino acid acetylation / regulation of chromosome organization / rRNA metabolic process / axonal transport of mitochondrion / regulation of mitochondrial fission / axon development / intracellular distribution of mitochondria / central nervous system neuron development / regulation of microtubule polymerization / microtubule polymerization / minor groove of adenine-thymine-rich DNA binding / lipoprotein particle binding / dynactin binding / negative regulation of mitochondrial membrane potential / glial cell projection / apolipoprotein binding / protein polymerization / negative regulation of mitochondrial fission / axolemma / regulation of microtubule polymerization or depolymerization / positive regulation of axon extension / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule cytoskeleton organization / synapse assembly / cytoplasmic microtubule organization / Activation of AMPK downstream of NMDARs / regulation of cellular response to heat / positive regulation of protein localization / supramolecular fiber organization / regulation of calcium-mediated signaling / axon cytoplasm / stress granule assembly / somatodendritic compartment / cellular response to brain-derived neurotrophic factor stimulus / positive regulation of microtubule polymerization / phosphatidylinositol binding / nuclear periphery / positive regulation of superoxide anion generation / protein phosphatase 2A binding / regulation of autophagy / astrocyte activation / cellular response to reactive oxygen species / response to lead ion / Hsp90 protein binding / microglial cell activation / synapse organization / cellular response to nerve growth factor stimulus / : / protein homooligomerization / regulation of synaptic plasticity / PKR-mediated signaling / memory / microtubule cytoskeleton organization / SH3 domain binding / cytoplasmic ribonucleoprotein granule / neuron projection development / microtubule cytoskeleton / cell-cell signaling / single-stranded DNA binding / actin binding / protein-folding chaperone binding / cellular response to heat / protein-macromolecule adaptor activity / cell body / growth cone / double-stranded DNA binding / microtubule binding / sequence-specific DNA binding / microtubule / dendritic spine / amyloid fibril formation / 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
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: 2.31 Å
AuthorsKunach P / Shahmoradian SH / Diamond MI / Rosa-Neto P
Funding support United States, Canada, 4 items
OrganizationGrant numberCountry
Cancer Prevention and Research Institute of Texas (CPRIT)RP170644 United States
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)R35GM122481 United States
Canadian Institutes of Health Research (CIHR)MOP-11-51-31 Canada
Canadian Institutes of Health Research (CIHR)152985 Canada
Citation
Journal: Nat Commun / Year: 2024
Title: Cryo-EM structure of Alzheimer's disease tau filaments with PET ligand MK-6240.
Authors: Peter Kunach / Jaime Vaquer-Alicea / Matthew S Smith / Jim Monistrol / Robert Hopewell / Luc Moquin / Joseph Therriault / Cecile Tissot / Nesrine Rahmouni / Gassan Massarweh / Jean-Paul ...Authors: Peter Kunach / Jaime Vaquer-Alicea / Matthew S Smith / Jim Monistrol / Robert Hopewell / Luc Moquin / Joseph Therriault / Cecile Tissot / Nesrine Rahmouni / Gassan Massarweh / Jean-Paul Soucy / Marie-Christine Guiot / Brian K Shoichet / Pedro Rosa-Neto / Marc I Diamond / Sarah H Shahmoradian /
Abstract: Positron Emission Tomography (PET) ligands have advanced Alzheimer's disease (AD) diagnosis and treatment. Using autoradiography and cryo-EM, we identify AD brain tissue with elevated tau burden, ...Positron Emission Tomography (PET) ligands have advanced Alzheimer's disease (AD) diagnosis and treatment. Using autoradiography and cryo-EM, we identify AD brain tissue with elevated tau burden, purify filaments, and determine the structure of second-generation high avidity PET ligand MK-6240 at 2.31 Å resolution, which bound at a 1:1 ratio within the cleft of tau paired-helical filament (PHF), engaging with glutamine 351, lysine 353, and isoleucine 360. This information elucidates the basis of MK-6240 PET in quantifying PHF deposits in AD and may facilitate the structure-based design of superior ligands against tau amyloids.
#1: Journal: Biorxiv / Year: 2023
Title: Alzheimer's disease PHF complexed with PET ligand MK-6240
Authors: Kunach P / Shahmoradian SH / Diamond MI / Rosa-Neto P
History
DepositionOct 23, 2023-
Header (metadata) releaseSep 4, 2024-
Map releaseSep 4, 2024-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_42463.png

Downloads & links

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Map

FileDownload / File: emd_42463.map.gz / Format: CCP4 / Size: 149.9 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 340 pix.
= 282.2 Å		0.83 Å/pix.
x 340 pix.
= 282.2 Å		0.83 Å/pix.
x 340 pix.
= 282.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.01
Minimum - Maximum-0.019291386 - 0.053804114
Average (Standard dev.)0.00030382146 (±0.0026364266)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions340340340
Spacing340340340
CellA=B=C: 282.19998 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_42463_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Microtubule-associated protein tau

EntireName: Microtubule-associated protein tau
Components
  • Tissue: Microtubule-associated protein tau
    • Protein or peptide: Microtubule-associated protein tau
  • Ligand: 6-fluoro-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine

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Supramolecule #1: Microtubule-associated protein tau

SupramoleculeName: Microtubule-associated protein tau / type: tissue / 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: 6 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 8.184412 KDa
SequenceString:
SVQIVYKPVD LSKVTSKCGS LGNIHHKPGG GQVEVKSEKL DFKDRVQSKI GSLDNITHVP GGGNKKIETH KLTFR

UniProtKB: Microtubule-associated protein tau

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Macromolecule #2: 6-fluoro-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine

MacromoleculeName: 6-fluoro-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine
type: ligand / ID: 2 / Number of copies: 6 / Formula: X6R
Molecular weightTheoretical: 278.284 Da

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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
GridModel: UltrAuFoil R1.2/1.3 / Material: COPPER / Mesh: 300
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 19 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 grids imaged: 1 / Number real images: 8037 / Average exposure time: 5.4 sec. / Average electron dose: 1.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Calibrated magnification: 105000 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.8 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 2.38 Å
Applied symmetry - Helical parameters - Δ&Phi: 179.46 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 2.31 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4.0) / Number images used: 32986
Segment selectionNumber selected: 1533788 / Software - Name: RELION (ver. 4.0)
Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE / Details: 179.46
FSC plot (resolution estimation)

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