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- PDB-8uq7: Alzheimer's disease PHF complexed with PET ligand MK-6240 -

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Basic information

Entry
Database: PDB / ID: 8uq7
TitleAlzheimer's disease PHF complexed with PET ligand MK-6240
ComponentsMicrotubule-associated protein tau
KeywordsPROTEIN FIBRIL / MK-6240 PET Ligand / AD PHF
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 / negative regulation of tubulin deacetylation / phosphatidylinositol bisphosphate binding ...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 / negative regulation of tubulin deacetylation / phosphatidylinositol bisphosphate binding / generation of neurons / rRNA metabolic process / axonal transport of mitochondrion / regulation of mitochondrial fission / axon development / regulation of chromosome organization / central nervous system neuron development / intracellular distribution of mitochondria / 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 / main axon / apolipoprotein binding / protein polymerization / axolemma / glial cell projection / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / negative regulation of mitochondrial fission / neurofibrillary tangle assembly / positive regulation of axon extension / regulation of cellular response to heat / synapse assembly / Activation of AMPK downstream of NMDARs / regulation of long-term synaptic depression / positive regulation of superoxide anion generation / positive regulation of protein localization / cellular response to brain-derived neurotrophic factor stimulus / supramolecular fiber organization / cytoplasmic microtubule organization / somatodendritic compartment / regulation of calcium-mediated signaling / axon cytoplasm / positive regulation of microtubule polymerization / astrocyte activation / phosphatidylinositol binding / nuclear periphery / stress granule assembly / protein phosphatase 2A binding / regulation of microtubule cytoskeleton organization / cellular response to reactive oxygen species / microglial cell activation / Hsp90 protein binding / cellular response to nerve growth factor stimulus / synapse organization / protein homooligomerization / PKR-mediated signaling / regulation of synaptic plasticity / response to lead ion / SH3 domain binding / microtubule cytoskeleton organization / memory / cytoplasmic ribonucleoprotein granule / neuron projection development / cell-cell signaling / single-stranded DNA binding / protein-folding chaperone binding / cellular response to heat / microtubule cytoskeleton / actin binding / growth cone / cell body / double-stranded DNA binding / protein-macromolecule adaptor activity / sequence-specific DNA binding / microtubule binding / dendritic spine / amyloid fibril formation / microtubule / learning or memory / neuron projection / regulation of autophagy / membrane raft / axon / negative regulation of gene expression / neuronal cell body / DNA damage response / dendrite / protein kinase binding / enzyme binding / mitochondrion / DNA binding / RNA binding / extracellular region / identical protein binding / nucleus / plasma membrane
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)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.31 Å
AuthorsKunach, P. / Shahmoradian, S.H. / Diamond, M.I. / Rosa-Neto, P.
Funding support United States, Canada, 4items
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, S.H. / Diamond, M.I. / Rosa-Neto, P.
History
DepositionOct 23, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 4, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2024Group: Data collection / Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / em_admin / pdbx_entry_details
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Microtubule-associated protein tau
B: Microtubule-associated protein tau
C: Microtubule-associated protein tau
D: Microtubule-associated protein tau
E: Microtubule-associated protein tau
F: Microtubule-associated protein tau
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,77612
Polymers49,1066
Non-polymers1,6706
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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


Mass: 8184.412 Da / Num. of mol.: 6 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P10636
#2: Chemical
ChemComp-X6R / 6-fluoro-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine


Mass: 278.284 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C16H11FN4 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

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

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Sample preparation

ComponentName: Microtubule-associated protein tau / Type: TISSUE / Entity ID: #1 / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 19 K

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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 FIELD / Calibrated magnification: 105000 X / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm / C2 aperture diameter: 70 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 5.4 sec. / Electron dose: 1 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 8037
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

EM software
IDNameVersionCategory
1RELION4particle selection
2RELION4image acquisition
4CTFFIND4.1CTF correction
9RELION4initial Euler assignment
12RELION43D reconstruction
CTF correctionType: NONE
Helical symmertyAngular rotation/subunit: 179.46 ° / Axial rise/subunit: 2.38 Å / Axial symmetry: C1
Particle selectionNum. of particles selected: 1533788
3D reconstructionResolution: 2.31 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 32986 / Symmetry type: HELICAL

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