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- PDB-9y0h: Insulin Degrading Enzyme Time-resolved O/O state -

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Basic information

Entry
Database: PDB / ID: 9y0h
TitleInsulin Degrading Enzyme Time-resolved O/O state
ComponentsCysteine-free Insulin-degrading enzyme
KeywordsHYDROLASE / M16A zinc metalloprotease
Function / homology
Function and homology information


insulysin / beta-endorphin binding / ubiquitin recycling / insulin catabolic process / insulin metabolic process / amyloid-beta clearance by cellular catabolic process / hormone catabolic process / bradykinin catabolic process / cytosolic proteasome complex / positive regulation of protein binding ...insulysin / beta-endorphin binding / ubiquitin recycling / insulin catabolic process / insulin metabolic process / amyloid-beta clearance by cellular catabolic process / hormone catabolic process / bradykinin catabolic process / cytosolic proteasome complex / positive regulation of protein binding / insulin binding / regulation of aerobic respiration / peptide catabolic process / peroxisomal matrix / amyloid-beta clearance / amyloid-beta metabolic process / Insulin receptor recycling / negative regulation of proteolysis / peptide binding / protein catabolic process / : / Peroxisomal protein import / antigen processing and presentation of endogenous peptide antigen via MHC class I / metalloendopeptidase activity / insulin receptor signaling pathway / positive regulation of protein catabolic process / peroxisome / amyloid-beta binding / virus receptor activity / endopeptidase activity / basolateral plasma membrane / Ub-specific processing proteases / external side of plasma membrane / protein-containing complex binding / cell surface / protein homodimerization activity / ATP hydrolysis activity / mitochondrion / proteolysis / : / extracellular exosome / zinc ion binding / ATP binding / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Peptidase M16, middle/third domain / Middle or third domain of peptidase_M16 / : / PQQ synthase PqqF-like, C-terminal lobe domain 4 / : / Peptidase M16, zinc-binding site / Insulinase family, zinc-binding region signature. / Peptidase M16, C-terminal / Peptidase M16 inactive domain / Peptidase M16, N-terminal ...Peptidase M16, middle/third domain / Middle or third domain of peptidase_M16 / : / PQQ synthase PqqF-like, C-terminal lobe domain 4 / : / Peptidase M16, zinc-binding site / Insulinase family, zinc-binding region signature. / Peptidase M16, C-terminal / Peptidase M16 inactive domain / Peptidase M16, N-terminal / Insulinase (Peptidase family M16) / Metalloenzyme, LuxS/M16 peptidase-like
Similarity search - Domain/homology
Insulin-degrading enzyme
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 5.1 Å
AuthorsMancl, J.M. / Tang, W.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
Citation
Journal: Elife / Year: 2026
Title: Characterization and modulation of human insulin degrading enzyme conformational dynamics to control enzyme activity.
Authors: Jordan M Mancl / Wenguang G Liang / Nicholas L Bayhi / Hui Wei / William C Budell / Joshua H Mendez / Tobin R Sosnick / Bridget Carragher / Clinton S Potter / Wei-Jen Tang /
Abstract: Insulin degrading enzyme (IDE) is a dimeric M16A zinc metalloprotease that degrades amyloidogenic peptides diverse in shape and sequence, including insulin and amyloid-β, to prevent toxic amyloid ...Insulin degrading enzyme (IDE) is a dimeric M16A zinc metalloprotease that degrades amyloidogenic peptides diverse in shape and sequence, including insulin and amyloid-β, to prevent toxic amyloid fibril formation. IDE has a hollow catalytic chamber formed by two ~55 kDa N- and C- domains (IDE-N and IDE-C, respectively), in which peptides bind, unfold, and are repositioned for proteolysis. IDE is known to transition between a closed state, poised for catalysis, and an open state, able to release cleavage products and bind a new substrate. Here, we present six cryo-EM structures of the IDE dimer at 3.0-5.1 Å resolution, obtained in the presence of a sub-saturating concentration of insulin. Combining cryo-EM heterogeneity analysis with all-atom molecular dynamics (MD) simulations, we identified the structural basis and key residues for IDE conformational dynamics that were not previously revealed by IDE static structures. Notably, R668 serves as a molecular latch mediating the open-close transition and facilitates key protein motions through charge-swapping interactions at the IDE-N/C interface. Our small-angle X-ray scattering analysis and enzymatic assays of an R668A mutant indicate a profound alteration of conformational dynamics and catalytic activity. By integrating coarse-grained MD simulations, our analysis reveals that IDE unfolds its substrates through the coordinated motion between IDE-N and IDE-C, as well as β-sheet formation between IDE and insulin. Additionally, our time-resolved cryo-EM analysis uncovers IDE allostery within the IDE dimer. Collectively, our findings demonstrate the strength of combining experimental and computational approaches to probe protein dynamics and pave the way for developing substrate-specific modulators of IDE activity.
#1: Journal: eLife / Year: 2025
Title: Characterization and modulation of human insulin degrading enzyme conformational dynamics to control enzyme activity
Authors: Mancl, J.M. / Liang, W.G. / Wei, H. / Carragher, B. / Potter, C.S. / Tang, W.J.
History
DepositionAug 28, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 6, 2026Provider: repository / Type: Initial release
Revision 1.0May 6, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0May 6, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 6, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 6, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0May 6, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jun 24, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin / Item: _em_admin.last_update
Revision 1.1Jun 24, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin / Data content type: EM metadata / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Cysteine-free Insulin-degrading enzyme
B: Cysteine-free Insulin-degrading enzyme


Theoretical massNumber of molelcules
Total (without water)234,1372
Polymers234,1372
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Cysteine-free Insulin-degrading enzyme / Abeta-degrading protease / Insulin protease / Insulinase / Insulysin


Mass: 117068.508 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IDE / Production host: Escherichia coli (E. coli) / References: UniProt: P14735, insulysin
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Cysteine-free Insulin-degrading enzyme / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: SPOTITON / Cryogen 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: 700 nm
Image recordingElectron dose: 65 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)
EM imaging opticsEnergyfilter slit width: 20 eV

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Processing

EM software
IDNameVersionCategory
1RELIONparticle selection
13RELION5.0.03D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 5.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 376750 / Symmetry type: POINT
RefinementHighest resolution: 5.1 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00315795
ELECTRON MICROSCOPYf_angle_d0.67721359
ELECTRON MICROSCOPYf_dihedral_angle_d5.1482048
ELECTRON MICROSCOPYf_chiral_restr0.0452300
ELECTRON MICROSCOPYf_plane_restr0.0052759

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