[English] 日本語
Yorodumi
- EMDB-42463: Alzheimer's disease PHF complexed with PET ligand MK-6240 -

+
Open data


ID or keywords:

Loading...

-
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 / 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 / Activation of AMPK downstream of NMDARs / synapse assembly / positive regulation of superoxide anion generation / regulation of long-term synaptic depression / positive regulation of protein localization / cellular response to brain-derived neurotrophic factor stimulus / supramolecular fiber organization / cytoplasmic microtubule organization / regulation of calcium-mediated signaling / somatodendritic compartment / axon cytoplasm / positive regulation of microtubule polymerization / astrocyte activation / phosphatidylinositol binding / stress granule assembly / nuclear periphery / regulation of microtubule cytoskeleton organization / protein phosphatase 2A binding / cellular response to reactive oxygen species / Hsp90 protein binding / microglial cell activation / 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 / growth cone / actin binding / cell body / double-stranded DNA binding / protein-macromolecule adaptor activity / microtubule binding / sequence-specific DNA 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)
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

-
Structure visualization

Supplemental images

emd_42463.png

Downloads & links

-
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 °

-
Supplemental data

-
Mask #1

Fileemd_42463_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Sample components

-
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

-
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)

-
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

-
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

-
Experimental details

-
Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

-
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

-
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

+
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)

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more