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- PDB-9b4j: Filament of D-TLKIVWS, a D-peptide that disaggregates Alzheimer's... -

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Basic information

Entry
Database: PDB / ID: 9b4j
TitleFilament of D-TLKIVWS, a D-peptide that disaggregates Alzheimer's Paired Helical Filaments, determined by Cryo-EM
ComponentsDTH-DLE-DLY-DIL-DVA-DTR-DSN
KeywordsUNKNOWN FUNCTION / Alzheimer's disease / Tau / fibril / cryo-EM / helix
Function / homologypolypeptide(D)
Function and homology information
Biological speciessynthetic construct (others)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsHou, K. / Ge, P. / Sawaya, M.R. / Eisenberg, D.S.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)1R01AG070895 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)RF1AG065407 United States
Department of Energy (DOE, United States)DOE-FC02-02ERG United States
CitationJournal: Nature / Year: 2025
Title: How short peptides disassemble tau fibrils in Alzheimer's disease.
Authors: Ke Hou / Peng Ge / Michael R Sawaya / Liisa Lutter / Joshua L Dolinsky / Yuan Yang / Yi Xiao Jiang / David R Boyer / Xinyi Cheng / Justin Pi / Jeffrey Zhang / Jiahui Lu / Romany Abskharon / ...Authors: Ke Hou / Peng Ge / Michael R Sawaya / Liisa Lutter / Joshua L Dolinsky / Yuan Yang / Yi Xiao Jiang / David R Boyer / Xinyi Cheng / Justin Pi / Jeffrey Zhang / Jiahui Lu / Romany Abskharon / Shixin Yang / Zhiheng Yu / Juli Feigon / David S Eisenberg /
Abstract: Reducing fibrous aggregates of the protein tau is a possible strategy for halting the progression of Alzheimer's disease (AD). Previously, we found that in vitro, the D-enantiomeric peptide (D- ...Reducing fibrous aggregates of the protein tau is a possible strategy for halting the progression of Alzheimer's disease (AD). Previously, we found that in vitro, the D-enantiomeric peptide (D-peptide) D-TLKIVWC disassembles ultra-stable tau fibrils extracted from the autopsied brains of individuals with AD (hereafter, these tau fibrils are referred to as AD-tau) into benign segments, with no energy source other than ambient thermal agitation. To consider D-peptide-mediated disassembly as a potential route to therapeutics for AD, it is essential to understand the mechanism and energy source of the disassembly action. Here, we show that the assembly of D-peptides into amyloid-like ('mock-amyloid') fibrils is essential for AD-tau disassembly. These mock-amyloid fibrils have a right-handed twist but are constrained to adopt a left-handed twist when templated in complex with AD-tau. The release of strain that accompanies the conversion of left-twisted to right-twisted, relaxed mock-amyloid produces a torque that is sufficient to break the local hydrogen bonding between tau molecules, and leads to the fragmentation of AD-tau. This strain-relief mechanism seems to operate in other examples of amyloid fibril disassembly, and could inform the development of first-in-class therapeutics for amyloid diseases.
History
DepositionMar 20, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 12, 2025Provider: repository / Type: Initial release
Revision 1.1Jul 9, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update
Revision 1.2Jul 23, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.pdbx_database_id_PubMed / _citation.title ..._citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _em_admin.last_update
Revision 1.3Sep 3, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: DTH-DLE-DLY-DIL-DVA-DTR-DSN
B: DTH-DLE-DLY-DIL-DVA-DTR-DSN
C: DTH-DLE-DLY-DIL-DVA-DTR-DSN
D: DTH-DLE-DLY-DIL-DVA-DTR-DSN
E: DTH-DLE-DLY-DIL-DVA-DTR-DSN
F: DTH-DLE-DLY-DIL-DVA-DTR-DSN
G: DTH-DLE-DLY-DIL-DVA-DTR-DSN
H: DTH-DLE-DLY-DIL-DVA-DTR-DSN
I: DTH-DLE-DLY-DIL-DVA-DTR-DSN
J: DTH-DLE-DLY-DIL-DVA-DTR-DSN
K: DTH-DLE-DLY-DIL-DVA-DTR-DSN
L: DTH-DLE-DLY-DIL-DVA-DTR-DSN
M: DTH-DLE-DLY-DIL-DVA-DTR-DSN
N: DTH-DLE-DLY-DIL-DVA-DTR-DSN
O: DTH-DLE-DLY-DIL-DVA-DTR-DSN
P: DTH-DLE-DLY-DIL-DVA-DTR-DSN
Q: DTH-DLE-DLY-DIL-DVA-DTR-DSN
R: DTH-DLE-DLY-DIL-DVA-DTR-DSN
S: DTH-DLE-DLY-DIL-DVA-DTR-DSN
T: DTH-DLE-DLY-DIL-DVA-DTR-DSN
U: DTH-DLE-DLY-DIL-DVA-DTR-DSN
V: DTH-DLE-DLY-DIL-DVA-DTR-DSN
W: DTH-DLE-DLY-DIL-DVA-DTR-DSN
X: DTH-DLE-DLY-DIL-DVA-DTR-DSN
Y: DTH-DLE-DLY-DIL-DVA-DTR-DSN
Z: DTH-DLE-DLY-DIL-DVA-DTR-DSN
0: DTH-DLE-DLY-DIL-DVA-DTR-DSN
1: DTH-DLE-DLY-DIL-DVA-DTR-DSN
2: DTH-DLE-DLY-DIL-DVA-DTR-DSN
3: DTH-DLE-DLY-DIL-DVA-DTR-DSN
4: DTH-DLE-DLY-DIL-DVA-DTR-DSN
5: DTH-DLE-DLY-DIL-DVA-DTR-DSN
6: DTH-DLE-DLY-DIL-DVA-DTR-DSN
7: DTH-DLE-DLY-DIL-DVA-DTR-DSN
8: DTH-DLE-DLY-DIL-DVA-DTR-DSN
9: DTH-DLE-DLY-DIL-DVA-DTR-DSN
a: DTH-DLE-DLY-DIL-DVA-DTR-DSN
b: DTH-DLE-DLY-DIL-DVA-DTR-DSN
c: DTH-DLE-DLY-DIL-DVA-DTR-DSN
d: DTH-DLE-DLY-DIL-DVA-DTR-DSN
e: DTH-DLE-DLY-DIL-DVA-DTR-DSN
f: DTH-DLE-DLY-DIL-DVA-DTR-DSN
g: DTH-DLE-DLY-DIL-DVA-DTR-DSN
h: DTH-DLE-DLY-DIL-DVA-DTR-DSN
i: DTH-DLE-DLY-DIL-DVA-DTR-DSN
j: DTH-DLE-DLY-DIL-DVA-DTR-DSN
k: DTH-DLE-DLY-DIL-DVA-DTR-DSN
l: DTH-DLE-DLY-DIL-DVA-DTR-DSN
m: DTH-DLE-DLY-DIL-DVA-DTR-DSN
n: DTH-DLE-DLY-DIL-DVA-DTR-DSN
o: DTH-DLE-DLY-DIL-DVA-DTR-DSN
p: DTH-DLE-DLY-DIL-DVA-DTR-DSN
q: DTH-DLE-DLY-DIL-DVA-DTR-DSN
r: DTH-DLE-DLY-DIL-DVA-DTR-DSN
s: DTH-DLE-DLY-DIL-DVA-DTR-DSN
t: DTH-DLE-DLY-DIL-DVA-DTR-DSN
u: DTH-DLE-DLY-DIL-DVA-DTR-DSN
v: DTH-DLE-DLY-DIL-DVA-DTR-DSN
w: DTH-DLE-DLY-DIL-DVA-DTR-DSN
x: DTH-DLE-DLY-DIL-DVA-DTR-DSN


Theoretical massNumber of molelcules
Total (without water)50,76260
Polymers50,76260
Non-polymers00
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: Polypeptide(D) ...
DTH-DLE-DLY-DIL-DVA-DTR-DSN


Mass: 846.026 Da / Num. of mol.: 60 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
Has ligand of interestN
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: D-peptide TLKIVWS / Type: COMPLEX / Entity ID: all / Source: SYNTHETIC
Molecular weightExperimental value: NO
Source (natural)Organism: synthetic construct (others)
Buffer solutionpH: 9.07 / Details: Dissolved in de-ionized water
SpecimenConc.: 10 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 295 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 / Nominal magnification: 81000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 1800 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1crYOLOparticle selection
2Leginonimage acquisition
4CTFFINDCTF correction
9PHENIXmodel refinement
11RELION4final Euler assignment
12RELION4classification
13RELION43D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 3.509 ° / Axial rise/subunit: 9.558 Å / Axial symmetry: C1
Particle selectionNum. of particles selected: 454000
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 32435 / Symmetry type: HELICAL
Atomic model buildingProtocol: AB INITIO MODEL / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0073660
ELECTRON MICROSCOPYf_angle_d0.9944980
ELECTRON MICROSCOPYf_dihedral_angle_d17.1561200
ELECTRON MICROSCOPYf_chiral_restr2.216660
ELECTRON MICROSCOPYf_plane_restr0.002480

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