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- PDB-9gzp: WT-IAPP cryo-EM structure Type LL - control reaction -

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Basic information

Entry
Database: PDB / ID: 9gzp
TitleWT-IAPP cryo-EM structure Type LL - control reaction
ComponentsIslet amyloid polypeptide
KeywordsPROTEIN FIBRIL / Amyloid / IAPP / amylin / aggregation / type-2 diabetes / polymorph
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 / positive regulation of calcium-mediated signaling / osteoclast differentiation / 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 speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsWilkinson, M. / Taylor, A.I.P. / Xu, Y. / Chakraborty, P. / Brinkworth, A. / Willis, L.F. / Zhuravleva, A. / Ranson, N.A. / Foster, R. / Radford, S.E.
Funding support United Kingdom, 2items
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, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 5, 2025Provider: repository / Type: Initial release
Revision 1.0Mar 5, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 5, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Mar 5, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 5, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 5, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 5, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Apr 16, 2025Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Islet amyloid polypeptide
B: Islet amyloid polypeptide
C: Islet amyloid polypeptide
D: Islet amyloid polypeptide
E: Islet amyloid polypeptide
F: Islet amyloid polypeptide
G: Islet amyloid polypeptide
H: Islet amyloid polypeptide
I: Islet amyloid polypeptide
J: Islet amyloid polypeptide
K: Islet amyloid polypeptide
L: Islet amyloid polypeptide


Theoretical massNumber of molelcules
Total (without water)46,88812
Polymers46,88812
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein/peptide
Islet amyloid polypeptide


Mass: 3907.312 Da / Num. of mol.: 12 / Source method: obtained synthetically / Details: Synthesised with C-terminal amidation / Source: (synth.) Homo sapiens (human) / References: UniProt: P10997
Has ligand of interestN
Has protein modificationY

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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: Amyloid fibril with helical symmetry / Type: COMPLEX / Entity ID: all / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: synthetic construct (others)
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
1160 mMammonium acetateNH4CH3CO21
21 % (v/v)DMSO(CH3)2SO1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: 30 uM IAPP
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: EMS Lacey Carbon
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 279 K

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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: 2400 nm / Nominal defocus min: 1200 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 43 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 2927
Image scansWidth: 4096 / Height: 4096

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Processing

EM software
IDNameVersionCategoryDetails
1crYOLO1.8particle selection
2EPUimage acquisition
4CTFFIND4CTF correction
7Coot0.8.9model fittingbuilt de novo into density
9RELION4initial Euler assignment
10RELION4final Euler assignment
11RELION4classification
12RELION43D reconstruction
13PHENIX1.17.1_3660:model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 179.38 ° / Axial rise/subunit: 2.43 Å / Axial symmetry: C1
Particle selectionNum. of particles selected: 749724
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 19396 / Symmetry type: HELICAL
Atomic model buildingB value: 80 / Protocol: FLEXIBLE FIT / Space: REAL / Target criteria: cross-correlation coefficient
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0072100
ELECTRON MICROSCOPYf_angle_d0.9222856
ELECTRON MICROSCOPYf_dihedral_angle_d8.735648
ELECTRON MICROSCOPYf_chiral_restr0.082336
ELECTRON MICROSCOPYf_plane_restr0.003372

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