6B70

Cryo-EM structure of human insulin degrading enzyme in complex with FAB H11-E heavy chain, FAB H11-E light chain and insulin


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.70 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Ensemble cryoEM elucidates the mechanism of insulin capture and degradation by human insulin degrading enzyme.

Zhang, Z.Liang, W.G.Bailey, L.J.Tan, Y.Z.Wei, H.Wang, A.Farcasanu, M.Woods, V.A.McCord, L.A.Lee, D.Shang, W.Deprez-Poulain, R.Deprez, B.Liu, D.R.Koide, A.Koide, S.Kossiakoff, A.A.Li, S.Carragher, B.Potter, C.S.Tang, W.J.

(2018) Elife 7

  • DOI: https://doi.org/10.7554/eLife.33572
  • Primary Citation of Related Structures:  
    5WOB, 6B3Q, 6B70, 6B7Y, 6B7Z, 6BF6, 6BF7, 6BF8, 6BF9, 6BFC

  • PubMed Abstract: 

    Insulin degrading enzyme (IDE) plays key roles in degrading peptides vital in type two diabetes, Alzheimer's, inflammation, and other human diseases. However, the process through which IDE recognizes peptides that tend to form amyloid fibrils remained unsolved. We used cryoEM to understand both the apo- and insulin-bound dimeric IDE states, revealing that IDE displays a large opening between the homologous ~55 kDa N- and C-terminal halves to allow selective substrate capture based on size and charge complementarity. We also used cryoEM, X-ray crystallography, SAXS, and HDX-MS to elucidate the molecular basis of how amyloidogenic peptides stabilize the disordered IDE catalytic cleft, thereby inducing selective degradation by substrate-assisted catalysis. Furthermore, our insulin-bound IDE structures explain how IDE processively degrades insulin by stochastically cutting either chain without breaking disulfide bonds. Together, our studies provide a mechanism for how IDE selectively degrades amyloidogenic peptides and offers structural insights for developing IDE-based therapies.


  • Organizational Affiliation

    National Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, United States.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Insulin-degrading enzyme
A, B
966Homo sapiensMutation(s): 0 
Gene Names: IDE
EC: 3.4.24.56
UniProt & NIH Common Fund Data Resources
Find proteins for P14735 (Homo sapiens)
Explore P14735 
Go to UniProtKB:  P14735
PHAROS:  P14735
GTEx:  ENSG00000119912 
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UniProt GroupP14735
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
FAB H11-E heavy chain
C, E
218Mus musculusHomo sapiens
This entity is chimeric
Mutation(s): 0 
UniProt
Find proteins for P0DOX5 (Homo sapiens)
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UniProt GroupP0DOX5
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
FAB H11-E light chain
D, F
211Mus musculusHomo sapiens
This entity is chimeric
Mutation(s): 0 
UniProt
Find proteins for Q6GMX0 (Homo sapiens)
Explore Q6GMX0 
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UniProt GroupQ6GMX0
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  • Reference Sequence
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
InsulinG [auth a],
H [auth c]
110Homo sapiensMutation(s): 0 
Gene Names: INS
UniProt & NIH Common Fund Data Resources
Find proteins for P01308 (Homo sapiens)
Explore P01308 
Go to UniProtKB:  P01308
PHAROS:  P01308
GTEx:  ENSG00000254647 
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UniProt GroupP01308
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Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.70 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 
EM Software:
TaskSoftware PackageVersion
RECONSTRUCTIONRELION2.1
MODEL REFINEMENTPHENIXPhenix-1.12-2829

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM103310
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM81539
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM121964
Simons FoundationUnited States349247

Revision History  (Full details and data files)

  • Version 1.0: 2017-12-27
    Type: Initial release
  • Version 1.1: 2018-01-17
    Changes: Author supporting evidence
  • Version 1.2: 2018-04-11
    Changes: Data collection, Database references
  • Version 1.3: 2020-01-01
    Changes: Author supporting evidence
  • Version 1.4: 2021-04-28
    Changes: Derived calculations