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- EMDB-40305: Cryo-EM structure of insulin amyloid-like fibril that is composed... -

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Entry
Database: EMDB / ID: EMD-40305
TitleCryo-EM structure of insulin amyloid-like fibril that is composed of two antiparallel protofilaments
Map dataCryo-EM structure of insulin amyloid-like fibril that is composed of two antiparallel protofilaments.
Sample
  • Complex: Cryo-EM structure of insulin amyloid-like fibril that is composed of two antiparallel protofilaments
    • Protein or peptide: Insulin B chain
    • Protein or peptide: Insulin A chain
Keywordsamyloid-like fibril / SIGNALING PROTEIN
Function / homology
Function and homology information


negative regulation of glycogen catabolic process / positive regulation of nitric oxide mediated signal transduction / negative regulation of fatty acid metabolic process / negative regulation of feeding behavior / Signaling by Insulin receptor / IRS activation / regulation of protein secretion / Insulin processing / positive regulation of peptide hormone secretion / positive regulation of respiratory burst ...negative regulation of glycogen catabolic process / positive regulation of nitric oxide mediated signal transduction / negative regulation of fatty acid metabolic process / negative regulation of feeding behavior / Signaling by Insulin receptor / IRS activation / regulation of protein secretion / Insulin processing / positive regulation of peptide hormone secretion / positive regulation of respiratory burst / negative regulation of acute inflammatory response / Regulation of gene expression in beta cells / alpha-beta T cell activation / positive regulation of dendritic spine maintenance / Synthesis, secretion, and deacylation of Ghrelin / activation of protein kinase B activity / negative regulation of protein secretion / negative regulation of gluconeogenesis / positive regulation of glycogen biosynthetic process / fatty acid homeostasis / Signal attenuation / positive regulation of insulin receptor signaling pathway / negative regulation of respiratory burst involved in inflammatory response / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / negative regulation of lipid catabolic process / positive regulation of lipid biosynthetic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / regulation of protein localization to plasma membrane / nitric oxide-cGMP-mediated signaling / transport vesicle / COPI-mediated anterograde transport / positive regulation of nitric-oxide synthase activity / Insulin receptor recycling / negative regulation of reactive oxygen species biosynthetic process / positive regulation of brown fat cell differentiation / insulin-like growth factor receptor binding / NPAS4 regulates expression of target genes / neuron projection maintenance / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / positive regulation of glycolytic process / positive regulation of cytokine production / endosome lumen / positive regulation of long-term synaptic potentiation / acute-phase response / positive regulation of protein secretion / positive regulation of D-glucose import across plasma membrane / insulin receptor binding / positive regulation of cell differentiation / Regulation of insulin secretion / wound healing / positive regulation of neuron projection development / hormone activity / regulation of synaptic plasticity / negative regulation of protein catabolic process / positive regulation of protein localization to nucleus / Golgi lumen / vasodilation / cognition / glucose metabolic process / insulin receptor signaling pathway / cell-cell signaling / glucose homeostasis / regulation of protein localization / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / protease binding / secretory granule lumen / positive regulation of canonical NF-kappaB signal transduction / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of MAPK cascade / positive regulation of cell migration / G protein-coupled receptor signaling pathway / endoplasmic reticulum lumen / Amyloid fiber formation / Golgi membrane / negative regulation of gene expression / positive regulation of cell population proliferation / positive regulation of gene expression / regulation of DNA-templated transcription / extracellular space / extracellular region / identical protein binding
Similarity search - Function
Insulin / Insulin family / Insulin-like / Insulin/IGF/Relaxin family / Insulin / insulin-like growth factor / relaxin family. / Insulin, conserved site / Insulin family signature. / Insulin-like superfamily
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsWang LW / Hall C / Uchikawa E / Chen DL / Choi E / Zhang XW / Bai XC
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM130289 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM136976 United States
CitationJournal: Sci Adv / Year: 2023
Title: Structural basis of insulin fibrillation.
Authors: Liwei Wang / Catherine E Hall / Emiko Uchikawa / Dailu Chen / Eunhee Choi / Xuewu Zhang / Xiao-Chen Bai /
Abstract: Insulin is a hormone responsible for maintaining normal glucose levels by activating insulin receptor (IR) and is the primary treatment for diabetes. However, insulin is prone to unfolding and ...Insulin is a hormone responsible for maintaining normal glucose levels by activating insulin receptor (IR) and is the primary treatment for diabetes. However, insulin is prone to unfolding and forming cross-β fibers. Fibrillation complicates insulin storage and therapeutic application. Molecular details of insulin fibrillation remain unclear, hindering efforts to prevent fibrillation process. Here, we characterized insulin fibrils using cryo-electron microscopy (cryo-EM), showing multiple forms that contain one or more of the protofilaments containing both the A and B chains of insulin linked by disulfide bonds. We solved the cryo-EM structure of one of the fibril forms composed of two protofilaments at 3.2-Å resolution, which reveals both the β sheet conformation of the protofilament and the packing interaction between them that underlie the fibrillation. On the basis of this structure, we designed several insulin mutants that display reduced fibrillation while maintaining native IR signaling activity. These designed insulin analogs may be developed into more effective therapeutics for type 1 diabetes.
History
DepositionApr 3, 2023-
Header (metadata) releaseAug 30, 2023-
Map releaseAug 30, 2023-
UpdateJun 4, 2025-
Current statusJun 4, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40305.png

Downloads & links

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Map

FileDownload / File: emd_40305.map.gz / Format: CCP4 / Size: 33.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of insulin amyloid-like fibril that is composed of two antiparallel protofilaments.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 206 pix.
= 170.98 Å		0.83 Å/pix.
x 206 pix.
= 170.98 Å		0.83 Å/pix.
x 206 pix.
= 170.98 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.017
Minimum - Maximum-0.04264341 - 0.073963016
Average (Standard dev.)0.00015444584 (±0.0022375959)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions206206206
Spacing206206206
CellA=B=C: 170.98 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Cryo-EM structure of insulin amyloid-like fibril that is...

Fileemd_40305_half_map_1.map
AnnotationCryo-EM structure of insulin amyloid-like fibril that is composed of two antiparallel protofilaments. Half map 1.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Cryo-EM structure of insulin amyloid-like fibril that is...

Fileemd_40305_half_map_2.map
AnnotationCryo-EM structure of insulin amyloid-like fibril that is composed of two antiparallel protofilaments. 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 : Cryo-EM structure of insulin amyloid-like fibril that is composed...

EntireName: Cryo-EM structure of insulin amyloid-like fibril that is composed of two antiparallel protofilaments
Components
  • Complex: Cryo-EM structure of insulin amyloid-like fibril that is composed of two antiparallel protofilaments
    • Protein or peptide: Insulin B chain
    • Protein or peptide: Insulin A chain

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Supramolecule #1: Cryo-EM structure of insulin amyloid-like fibril that is composed...

SupramoleculeName: Cryo-EM structure of insulin amyloid-like fibril that is composed of two antiparallel protofilaments
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Insulin B chain

MacromoleculeName: Insulin B chain / type: protein_or_peptide / ID: 1 / Number of copies: 16 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 3.433953 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
FVNQHLCGSH LVEALYLVCG ERGFFYTPKT

UniProtKB: Insulin

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Macromolecule #2: Insulin A chain

MacromoleculeName: Insulin A chain / type: protein_or_peptide / ID: 2 / Number of copies: 16 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 2.383698 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
GIVEQCCTSI CSLYQLENYC N

UniProtKB: Insulin

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation statefilament

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Sample preparation

Concentration1 mg/mL
BufferpH: 2
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Average exposure time: 8.0 sec. / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.6 µm / Nominal defocus min: 1.6 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

Particle selectionNumber selected: 551345
CTF correctionSoftware - Name: Gctf / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: Generated from RELION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 56537
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final 3D classificationSoftware - Name: RELION
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-8sbd:
Cryo-EM structure of insulin amyloid-like fibril that is composed of two antiparallel protofilaments

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