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- PDB-8qvp: Cryo-EM structure of human islet amyloid polypeptide (hIAPP) muta... -

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Basic information

Entry
Database: PDB / ID: 8qvp
TitleCryo-EM structure of human islet amyloid polypeptide (hIAPP) mutant S29P, polymorph 1
ComponentsIslet amyloid polypeptide
KeywordsPROTEIN FIBRIL / amyloid
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 / Amyloid fiber formation / receptor ligand activity / 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: 3.75 Å
AuthorsOoi, S.A. / Valli, D. / Maj, M.
Funding support Sweden, 2items
OrganizationGrant numberCountry
Swedish Research CouncilVR 2020-05403 Sweden
Other privateSwedish Society for Medical Research (S20-0156) Sweden
CitationJournal: J Mol Biol / Year: 2025
Title: Cryo-EM exposes diverse polymorphism in IAPP mutants to guide the rational design of peptide-based therapeutics.
Authors: Saik Ann Ooi / Dylan Valli / Mikołaj I Kuska / Helena Marí / Himanshu Chaudhary / Weixiao Yuan Wahlgren / Sebastian Westenhoff / Alesia A Tietze / Anna Novials / Joan-Marc Servitja / Michał Maj /
Abstract: In the pursuit of potential therapeutic agents for type 2 diabetes, non-amyloidogenic forms of the human Islet Amyloid Polypeptide (hIAPP) containing site-specific mutations are of significant ...In the pursuit of potential therapeutic agents for type 2 diabetes, non-amyloidogenic forms of the human Islet Amyloid Polypeptide (hIAPP) containing site-specific mutations are of significant interest. In the present study, we dissect the three proline mutations present in the core region of the non-amyloidogenic rat IAPP into single-point mutations at A25P, S28P, and S29P sites. We apply high-resolution cryo-electron microscopy and solve the structures of 6 polymorphs formed by these mutants, revealing the peptide's self-assembly patterns and identifying critical interactions that reinforce these structures in the presence of the β-sheet breaker. A unique trimeric aggregate with C3 symmetry was identified in the A25P mutant, which we resolved with a 3.05 Å resolution, while asymmetric trimeric assemblies were observed in the other mutants. Guided by the high-resolution structural models of A25P and S28P fibrils obtained in our study, we successfully designed novel non-amyloidogenic mutants of IAPP with potential therapeutic value. Our findings demonstrate the immense potential of structure-based approaches in developing effective therapeutics against amyloid diseases.
History
DepositionNov 2, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 13, 2025Provider: repository / Type: Initial release
Revision 1.0Aug 13, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Aug 13, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Aug 13, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Aug 13, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
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Revision 1.1Feb 11, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: Islet amyloid polypeptide
I: Islet amyloid polypeptide
J: Islet amyloid polypeptide
K: Islet amyloid polypeptide
L: Islet amyloid polypeptide
M: Islet amyloid polypeptide
N: Islet amyloid polypeptide
O: Islet amyloid polypeptide
P: Islet amyloid polypeptide
Q: Islet amyloid polypeptide


Theoretical massNumber of molelcules
Total (without water)39,17310
Polymers39,17310
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: 3917.349 Da / Num. of mol.: 10 / Mutation: S29P / Source method: obtained synthetically / 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: Human islet amyloid polypeptide (hIAPP) / Type: CELL / Entity ID: all / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: synthetic construct (others)
Buffer solutionpH: 7.4
SpecimenConc.: 0.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE-PROPANE / Humidity: 100 % / Chamber temperature: 277.15 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 magnification: 165000 X / Nominal defocus max: 2400 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 58 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1RELIONparticle selection
2EPU2.12.1image acquisition
4CTFFINDCTF correction
7Coot0.9.8.8model fitting
9PHENIX1.21model refinement
13RELION4.0.03D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -3.28 ° / Axial rise/subunit: 4.76 Å / Axial symmetry: C2
3D reconstructionResolution: 3.75 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 4930 / Symmetry type: HELICAL

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