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- EMDB-51733: WT-IAPP cryo-EM structure Type LLU - control reaction -

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Basic information

Entry
Database: EMDB / ID: EMD-51733
TitleWT-IAPP cryo-EM structure Type LLU - control reaction
Map dataPostprocessed, sharpened map
Sample
  • Complex: Amyloid fibril with helical symmetry
    • Protein or peptide: Islet amyloid polypeptide
KeywordsAmyloid / IAPP / amylin / aggregation / type-2 diabetes / polymorph / PROTEIN FIBRIL
Function / homology
Function and homology information


amylin receptor 3 signaling pathway / amylin receptor 2 signaling pathway / amylin receptor 1 signaling pathway / amylin receptor signaling pathway / Calcitonin-like ligand receptors / negative regulation of amyloid fibril formation / negative regulation of bone resorption / eating behavior / negative regulation of osteoclast differentiation / Regulation of gene expression in beta cells ...amylin receptor 3 signaling pathway / amylin receptor 2 signaling pathway / amylin receptor 1 signaling pathway / amylin receptor signaling pathway / Calcitonin-like ligand receptors / negative regulation of amyloid fibril formation / negative regulation of bone resorption / eating behavior / negative regulation of osteoclast differentiation / Regulation of gene expression in beta cells / positive regulation of cAMP/PKA signal transduction / bone resorption / negative regulation of protein-containing complex assembly / sensory perception of pain / osteoclast differentiation / positive regulation of calcium-mediated signaling / hormone activity / cell-cell signaling / amyloid-beta binding / G alpha (s) signalling events / positive regulation of MAPK cascade / positive regulation of apoptotic process / receptor ligand activity / Amyloid fiber formation / signaling receptor binding / neuronal cell body / apoptotic process / lipid binding / signal transduction / extracellular space / extracellular region / identical protein binding
Similarity search - Function
Islet amyloid polypeptide / Calcitonin-like / Calcitonin peptide-like / Calcitonin, conserved site / Calcitonin / CGRP / IAPP family signature. / calcitonin / Calcitonin/adrenomedullin / Calcitonin / CGRP / IAPP family
Similarity search - Domain/homology
Islet amyloid polypeptide
Similarity search - Component
Biological speciessynthetic construct (others) / Homo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsWilkinson M / Taylor AIP / Xu Y / Chakraborty P / Brinkworth A / Willis LF / Zhuravleva A / Ranson NA / Foster R / Radford SE
Funding support United Kingdom, 2 items
OrganizationGrant numberCountry
Wellcome Trust204963 United Kingdom
Royal SocietyRSRP/R1/211057 United Kingdom
CitationJournal: J Am Chem Soc / Year: 2025
Title: Kinetic Steering of Amyloid Formation and Polymorphism by Canagliflozin, a Type-2 Diabetes Drug.
Authors: Alexander I P Taylor / Yong Xu / Martin Wilkinson / Pijush Chakraborty / Alice Brinkworth / Leon F Willis / Anastasia Zhuravleva / Neil A Ranson / Richard Foster / Sheena E Radford /
Abstract: Amyloid formation is involved in widespread health conditions such as Alzheimer's disease, Parkinson's disease, and type-2 diabetes. Amyloid fibrils have a similar cross-β architecture, but fibrils ...Amyloid formation is involved in widespread health conditions such as Alzheimer's disease, Parkinson's disease, and type-2 diabetes. Amyloid fibrils have a similar cross-β architecture, but fibrils formed by a single protein sequence can have diverse structures, varying with time, self-assembly conditions, and sequence modifications. Fibril structure has been proposed to be diagnostic of disease, but why different structures result under different conditions, especially in vitro, remains elusive. We previously identified a small molecule, YX-I-1, which inhibits in vitro amyloid formation by islet amyloid polypeptide (IAPP), a peptide hormone whose amyloid formation is involved in type-2 diabetes. Here, using YX-I-1 as a lead, we identified regulator-approved drugs with similar structures by chemical similarity analysis and substructure searches and monitored the effect of 24 of these potential ligands on IAPP amyloid assembly in vitro. We show that one such compound, canagliflozin (Invokana), a type-2 diabetes drug already in clinical use, can strongly delay the kinetics of IAPP amyloid formation, an activity independent of its intended mode of action [sodium-glucose linked transporter 2 (SGLT2) inhibitor] that may have important therapeutic implications. Combining analysis of amyloid self-assembly kinetics, biophysical characterization of monomer and fibril binding, and cryo-EM of the assembly products, we show that YX-I-1 and canagliflozin target IAPP early in aggregation, remodeling the energy landscape of primary nucleation and profoundly altering the resulting fibril structures. Early binding events thus imprint long-lasting effects on the amyloid structures that form.
History
DepositionOct 4, 2024-
Header (metadata) releaseMar 5, 2025-
Map releaseMar 5, 2025-
UpdateApr 16, 2025-
Current statusApr 16, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_51733.png

Downloads & links

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Map

FileDownload / File: emd_51733.map.gz / Format: CCP4 / Size: 134.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationPostprocessed, sharpened map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.75 Å/pix.
x 328 pix.
= 244.36 Å		0.75 Å/pix.
x 328 pix.
= 244.36 Å		0.75 Å/pix.
x 328 pix.
= 244.36 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.745 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.008
Minimum - Maximum-0.01861604 - 0.035897914
Average (Standard dev.)0.00020189158 (±0.0017830534)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions328328328
Spacing328328328
CellA=B=C: 244.36 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: halfmap2

Fileemd_51733_half_map_1.map
Annotationhalfmap2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: halfmap1

Fileemd_51733_half_map_2.map
Annotationhalfmap1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Amyloid fibril with helical symmetry

EntireName: Amyloid fibril with helical symmetry
Components
  • Complex: Amyloid fibril with helical symmetry
    • Protein or peptide: Islet amyloid polypeptide

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Supramolecule #1: Amyloid fibril with helical symmetry

SupramoleculeName: Amyloid fibril with helical symmetry / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: synthetic construct (others)

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Macromolecule #1: Islet amyloid polypeptide

MacromoleculeName: Islet amyloid polypeptide / type: protein_or_peptide / ID: 1 / Details: Synthesised with C-terminal amidation / Number of copies: 18 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 3.907312 KDa
SequenceString:
KCNTATCATQ RLANFLVHSS NNFGAILSST NVGSNTY(NH2)

UniProtKB: Islet amyloid polypeptide

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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: 7.4
Component:
ConcentrationFormulaName
160.0 mMNH4CH3CO2ammonium acetate
1.0 % (v/v)(CH3)2SODMSO
GridModel: EMS Lacey Carbon / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: LACEY / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Time: 60 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 279 K / Instrument: FEI VITROBOT MARK IV
Details30 uM IAPP

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Number grids imaged: 1 / Number real images: 2927 / Average electron dose: 43.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.2 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.86 Å
Applied symmetry - Helical parameters - Δ&Phi: -1.07 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4) / Number images used: 12541
Segment selectionNumber selected: 749724 / Software - Name: crYOLO (ver. 1.8)
Startup modelType of model: INSILICO MODEL
In silico model: initial model generated from 2D class averages in the data
Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION (ver. 4)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

9gzp


Chain - Chain ID: A / Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Overall B value: 80 / Target criteria: cross-correlation coefficient
Output model

PDB-9gzs:
WT-IAPP cryo-EM structure Type LLU - control reaction

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