[English] 日本語
Yorodumi
- EMDB-29458: Alzheimer's disease paired-helical filament in complex with PET t... -

+
Open data


ID or keywords:

Loading...

-
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 / negative regulation of protein localization to mitochondrion / neurofibrillary tangle / microtubule lateral binding / axonal transport / tubulin complex / positive regulation of protein localization to synapse / phosphatidylinositol bisphosphate binding / generation of neurons ...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 / phosphatidylinositol bisphosphate binding / generation of neurons / axon development / axonal transport of mitochondrion / rRNA metabolic process / central nervous system neuron development / regulation of microtubule-based movement / regulation of mitochondrial fission / regulation of chromosome organization / 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 / apolipoprotein binding / regulation of calcium-mediated signaling / main axon / Caspase-mediated cleavage of cytoskeletal proteins / glial cell projection / regulation of microtubule polymerization or depolymerization / negative regulation of mitochondrial fission / axolemma / positive regulation of axon extension / neurofibrillary tangle assembly / protein polymerization / positive regulation of microtubule polymerization / regulation of cellular response to heat / positive regulation of protein localization / Activation of AMPK downstream of NMDARs / positive regulation of superoxide anion generation / cytoplasmic microtubule organization / cellular response to brain-derived neurotrophic factor stimulus / regulation of long-term synaptic depression / axon cytoplasm / supramolecular fiber organization / synapse assembly / somatodendritic compartment / astrocyte activation / nuclear periphery / phosphatidylinositol binding / protein phosphatase 2A binding / stress granule assembly / enzyme inhibitor activity / cellular response to reactive oxygen species / regulation of microtubule cytoskeleton organization / memory / microglial cell activation / cellular response to nerve growth factor stimulus / regulation of synaptic plasticity / Hsp90 protein binding / SH3 domain binding / synapse organization / regulation of autophagy / protein homooligomerization / microtubule cytoskeleton organization / PKR-mediated signaling / response to lead ion / neuron projection development / cytoplasmic ribonucleoprotein granule / microtubule cytoskeleton / cell-cell signaling / cellular response to heat / single-stranded DNA binding / growth cone / protein-folding chaperone binding / actin binding / cell body / double-stranded DNA binding / sequence-specific DNA binding / microtubule binding / amyloid fibril formation / dendritic spine / microtubule / learning or memory / protein-macromolecule adaptor activity / neuron projection / membrane raft / negative regulation of gene expression / axon / neuronal cell body / DNA damage response / dendrite / protein kinase binding / enzyme binding / mitochondrion / DNA binding / RNA binding / extracellular region / identical protein binding / nucleus
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

-
Structure visualization

Supplemental images

emd_29458.png

Downloads & links

-
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 °

-
Supplemental data

-
Half map: #1

Fileemd_29458_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: #2

Fileemd_29458_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Sample components

-
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

-
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)

-
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

-
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

-
Experimental details

-
Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

-
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

-
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

+
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)

+
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