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- PDB-9rax: The L1 amyloid-beta(1-40)fibril in the presence of anle138b (pre-... -

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Basic information

Entry
Database: PDB / ID: 9rax
TitleThe L1 amyloid-beta(1-40)fibril in the presence of anle138b (pre-treatment)
ComponentsAmyloid-beta A4 protein
KeywordsPROTEIN FIBRIL / amyloid-beta / fibril / anle138b
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)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.76 Å
AuthorsFrieg, B. / Han, M. / Griesinger, C. / Schroeder, G.F.
Funding support Germany, 3items
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, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 15, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Amyloid-beta A4 protein
B: Amyloid-beta A4 protein
C: Amyloid-beta A4 protein
D: Amyloid-beta A4 protein
E: Amyloid-beta A4 protein
F: Amyloid-beta A4 protein
G: Amyloid-beta A4 protein
H: Amyloid-beta A4 protein
I: Amyloid-beta A4 protein
J: Amyloid-beta A4 protein


Theoretical massNumber of molelcules
Total (without water)43,35910
Polymers43,35910
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1chain "A"
d_2ens_1chain "B"
d_3ens_1chain "C"
d_4ens_1chain "D"
d_5ens_1chain "E"
d_6ens_1chain "F"
d_7ens_1chain "G"
d_8ens_1chain "H"
d_9ens_1chain "I"
d_10ens_1chain "J"

NCS domain segments:

Component-ID: 1 / Ens-ID: ens_1 / Beg auth comp-ID: ASP / Beg label comp-ID: ASP / End auth comp-ID: VAL / End label comp-ID: VAL / Auth seq-ID: 1 - 40 / Label seq-ID: 1 - 40

Dom-IDAuth asym-IDLabel asym-ID
d_1AA
d_2BB
d_3CC
d_4DD
d_5EE
d_6FF
d_7GG
d_8HH
d_9II
d_10JJ

NCS oper:
IDCodeMatrixVector
1given(-0.99998111088, -0.00614378902013, 0.000178158241507), (0.00614373252806, -0.999981077193, -0.000315921635632), (0.000180095826129, -0.000314821111566, 0.999999934227)263.286182959, 261.722757955, 2.36853191544
2given(0.999924563825, 0.0122827789617, -5.18861365711E-7), (-0.0122827789597, 0.999924563818, 3.67058228705E-6), (5.63907175683E-7, -3.6639323329E-6, 0.999999999993)-1.60149698181, 1.62101562502, 4.70238552419
3given(-0.999834988007, -0.0180048772431, -0.00241270640113), (0.0180033962975, -0.999837724633, 0.000634131796345), (-0.00242373234347, 0.000590590247504, 0.999996888358)265.058656242, 260.067892139, 7.32259527561
4given(0.999699979841, 0.0244937926025, 6.65547763062E-5), (-0.0244937982182, 0.999699978313, 8.49146086225E-5), (-6.44549276174E-5, -8.65193117894E-5, 0.99999999418)-3.18222989852, 3.24370590654, 9.4226178861
5given(-0.999436976095, -0.0335282661885, 0.00125943633951), (0.0335241503816, -0.999432918069, -0.00315810403746), (0.00136460788873, -0.00311410441615, 0.999994220083)266.612844314, 258.083271372, 11.9794020171
6given(0.999321246504, 0.0368344235112, 0.000521086319574), (-0.0368342789198, 0.999321347218, -0.000284411548351), (-0.000531208818317, 0.000265024664182, 0.99999982379)-4.79357589712, 4.95010175964, 14.1424787707
7given(-0.999090499586, -0.0425971922801, -0.0019112423232), (0.0425962833257, -0.999092234302, 0.000513813312252), (-0.00193139436743, 0.000431934179328, 0.999998041572)268.142990792, 256.750630683, 16.6770139922
8given(0.99879348261, 0.0491078305382, 8.74496575678E-6), (-0.0491078306051, 0.998793482616, 7.60781375531E-6), (-8.36081157491E-6, -8.02808109274E-6, 0.999999999933)-6.28620648502, 6.60005166538, 18.8101658069
9given(-0.998472472401, -0.0552511834971, 0.000169056722977), (0.055251127899, -0.998472439293, -0.000317549925363), (0.000186343487766, -0.000307724284465, 0.999999935291)269.536238146, 255.076755108, 21.1747926353

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Components

#1: Protein/peptide
Amyloid-beta A4 protein


Mass: 4335.852 Da / Num. of mol.: 10
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: B4DM00
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: The L1 amyloid-beta(1-40)fibril in the presence of anle138b (pre-treatment)
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 6.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: NONE
Helical symmertyAngular rotation/subunit: 179.65 ° / Axial rise/subunit: 2.35 Å / Axial symmetry: C1
3D reconstructionResolution: 2.76 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 888252 / Symmetry type: HELICAL
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 65.3 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.01413120
ELECTRON MICROSCOPYf_angle_d2.08614190
ELECTRON MICROSCOPYf_chiral_restr0.101440
ELECTRON MICROSCOPYf_plane_restr0.0075560
ELECTRON MICROSCOPYf_dihedral_angle_d14.88641070
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AAELECTRON MICROSCOPYNCS constraints0.000686942310157
ens_1d_3AAELECTRON MICROSCOPYNCS constraints0.000615222624562
ens_1d_4AAELECTRON MICROSCOPYNCS constraints0.000708717899098
ens_1d_5AAELECTRON MICROSCOPYNCS constraints0.000692929203425
ens_1d_6AAELECTRON MICROSCOPYNCS constraints0.000701654078991
ens_1d_7AAELECTRON MICROSCOPYNCS constraints0.000714211549303
ens_1d_8AAELECTRON MICROSCOPYNCS constraints0.000701479694685
ens_1d_9AAELECTRON MICROSCOPYNCS constraints0.000690902793761
ens_1d_10AAELECTRON MICROSCOPYNCS constraints0.000699771825047

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