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- EMDB-53880: The L1 amyloid-beta(1-40)fibril in the presence of anle138b (post... -

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Basic information

Entry
Database: EMDB / ID: EMD-53880
TitleThe L1 amyloid-beta(1-40)fibril in the presence of anle138b (post-treatment)
Map dataThe L1 amyloid-beta(1-40)fibril in the presence of anle138b (post-treatment)
Sample
  • Complex: The L1 amyloid-beta(1-40)fibril in the presence of anle138b (post-treatment)
    • Protein or peptide: Amyloid-beta A4 protein
Keywordsamyloid-beta / fibril / anle138b / PROTEIN FIBRIL
Function / homology
Function and homology information


Golgi-associated vesicle / clathrin-coated pit / serine-type endopeptidase inhibitor activity / endocytosis / heparin binding / growth cone / perikaryon / early endosome / cell surface / endoplasmic reticulum ...Golgi-associated vesicle / clathrin-coated pit / serine-type endopeptidase inhibitor activity / endocytosis / heparin binding / growth cone / perikaryon / early endosome / cell surface / endoplasmic reticulum / extracellular region / nucleus / plasma membrane
Similarity search - Function
Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide / Beta-amyloid precursor protein C-terminal / Amyloidogenic glycoprotein, intracellular domain, conserved site / Beta-amyloid precursor protein C-terminus / Amyloid precursor protein (APP) intracellular domain signature. / Amyloidogenic glycoprotein, extracellular / Amyloidogenic glycoprotein, heparin-binding / Amyloidogenic glycoprotein, E2 domain ...Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide / Beta-amyloid precursor protein C-terminal / Amyloidogenic glycoprotein, intracellular domain, conserved site / Beta-amyloid precursor protein C-terminus / Amyloid precursor protein (APP) intracellular domain signature. / Amyloidogenic glycoprotein, extracellular / Amyloidogenic glycoprotein, heparin-binding / Amyloidogenic glycoprotein, E2 domain / E2 domain superfamily / Amyloidogenic glycoprotein, heparin-binding domain superfamily / Amyloid A4 N-terminal heparin-binding / E2 domain of amyloid precursor protein / Amyloid precursor protein (APP) E1 domain profile. / Amyloid precursor protein (APP) E2 domain profile. / amyloid A4 / Amyloidogenic glycoprotein / PH-like domain superfamily
Similarity search - Domain/homology
Amyloid-beta A4 protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 2.79 Å
AuthorsFrieg B / Han M / Griesinger C / Schroeder GF
Funding support Germany, 3 items
OrganizationGrant numberCountry
Max Planck Society Germany
Helmholtz Association Germany
German Research Foundation (DFG) Germany
CitationJournal: Nat Commun / Year: 2025
Title: Anle138b binds predominantly to the central cavity in lipidic Aβ₄₀ fibrils and modulates fibril formation.
Authors: Mookyoung Han / Benedikt Frieg / Dirk Matthes / Andrei Leonov / Sergey Ryazanov / Karin Giller / Evgeny Nimerovsky / Marianna Stampolaki / Kai Xue / Kerstin Overkamp / Christian Dienemann / ...Authors: Mookyoung Han / Benedikt Frieg / Dirk Matthes / Andrei Leonov / Sergey Ryazanov / Karin Giller / Evgeny Nimerovsky / Marianna Stampolaki / Kai Xue / Kerstin Overkamp / Christian Dienemann / Dietmar Riedel / Armin Giese / Stefan Becker / Bert L de Groot / Gunnar F Schröder / Loren B Andreas / Christian Griesinger /
Abstract: Alzheimer's disease is a specific neurodegenerative disorder, distinct from normal aging, with a growing unmet medical need. It is characterized by the accumulation of amyloid plaques in the brain, ...Alzheimer's disease is a specific neurodegenerative disorder, distinct from normal aging, with a growing unmet medical need. It is characterized by the accumulation of amyloid plaques in the brain, primarily consisting of amyloid beta (Aβ) fibrils. Therapeutic antibodies can slow down the disease, but are associated with potential severe side effects, motivating the development of small molecules to halt disease progression. This study investigates the interaction between the clinical drug candidate small molecule anle138b and lipidic Aβ₄₀ fibrils of type 1 (L1). L1 fibrils were previously shown to closely resemble fibrils from Alzheimer's patients. Using high-resolution structural biology techniques, including cryo-electron microscopy (cryo-EM), nuclear magnetic resonance (NMR) spectroscopy enhanced by dynamic nuclear polarization (DNP), and molecular dynamics (MD) simulations, we find that anle138b selectively binds to a cavity within the fibril. This structural insight provides a deeper understanding of a potential drug-binding mechanism at the atomic level and may inform the development of therapies and diagnostic approaches. In addition, anle138b reduces fibril formation in the presence of lipids by approximately 75%. This may suggest a mechanistic connection to its previously reported activity in animal models of Alzheimer's disease.
History
DepositionMay 21, 2025-
Header (metadata) releaseOct 15, 2025-
Map releaseOct 15, 2025-
UpdateOct 15, 2025-
Current statusOct 15, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_53880.png

Downloads & links

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Map

FileDownload / File: emd_53880.map.gz / Format: CCP4 / Size: 59.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationThe L1 amyloid-beta(1-40)fibril in the presence of anle138b (post-treatment)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 250 pix.
= 262.5 Å		1.05 Å/pix.
x 250 pix.
= 262.5 Å		1.05 Å/pix.
x 250 pix.
= 262.5 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.05 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.05
Minimum - Maximum-0.10370119 - 0.25883436
Average (Standard dev.)0.0017302713 (±0.011797488)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions250250250
Spacing250250250
CellA=B=C: 262.5 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: The L1 amyloid-beta(1-40)fibril in the presence of anle138b...

Fileemd_53880_half_map_1.map
AnnotationThe L1 amyloid-beta(1-40)fibril in the presence of anle138b (post-treatment) (half map 1)
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: The L1 amyloid-beta(1-40)fibril in the presence of anle138b...

Fileemd_53880_half_map_2.map
AnnotationThe L1 amyloid-beta(1-40)fibril in the presence of anle138b (post-treatment) (half map 2)
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : The L1 amyloid-beta(1-40)fibril in the presence of anle138b (post...

EntireName: The L1 amyloid-beta(1-40)fibril in the presence of anle138b (post-treatment)
Components
  • Complex: The L1 amyloid-beta(1-40)fibril in the presence of anle138b (post-treatment)
    • Protein or peptide: Amyloid-beta A4 protein

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Supramolecule #1: The L1 amyloid-beta(1-40)fibril in the presence of anle138b (post...

SupramoleculeName: The L1 amyloid-beta(1-40)fibril in the presence of anle138b (post-treatment)
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Amyloid-beta A4 protein

MacromoleculeName: Amyloid-beta A4 protein / type: protein_or_peptide / ID: 1 / Number of copies: 10 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 4.335852 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
DAEFRHDSGY EVHHQKLVFF AEDVGSNKGA IIGLMVGGVV

UniProtKB: Amyloid-beta A4 protein

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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: 6.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 2.35 Å
Applied symmetry - Helical parameters - Δ&Phi: 179.65 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 2.79 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 326836
CTF correctionType: NONE
Startup modelType of model: NONE / Details: Featureless cylinder
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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