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- PDB-7rzf: Insulin Degrading Enzyme O/pC -

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Basic information

Entry
Database: PDB / ID: 7rzf
TitleInsulin Degrading Enzyme O/pC
Components
  • Cysteine-free Insulin-degrading enzyme
  • Insulin A chain
  • Insulin B chain
KeywordsHYDROLASE / M16A zinc metalloprotease
Function / homology
Function and homology information


insulysin / ubiquitin recycling / insulin catabolic process / insulin metabolic process / amyloid-beta clearance by cellular catabolic process / hormone catabolic process / bradykinin catabolic process / insulin binding / negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process ...insulysin / ubiquitin recycling / insulin catabolic process / insulin metabolic process / amyloid-beta clearance by cellular catabolic process / hormone catabolic process / bradykinin catabolic process / insulin binding / negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / positive regulation of nitric oxide mediated signal transduction / negative regulation of fatty acid metabolic process / regulation of aerobic respiration / negative regulation of feeding behavior / peptide catabolic process / Signaling by Insulin receptor / IRS activation / Insulin processing / regulation of protein secretion / 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 / amyloid-beta clearance / regulation of amino acid metabolic process / peroxisomal matrix / negative regulation of respiratory burst involved in inflammatory response / positive regulation of dendritic spine maintenance / positive regulation of glycogen biosynthetic process / Synthesis, secretion, and deacylation of Ghrelin / negative regulation of protein secretion / regulation of protein localization to plasma membrane / amyloid-beta metabolic process / fatty acid homeostasis / negative regulation of lipid catabolic process / negative regulation of gluconeogenesis / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / COPI-mediated anterograde transport / positive regulation of lipid biosynthetic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / positive regulation of insulin receptor signaling pathway / nitric oxide-cGMP-mediated signaling / negative regulation of reactive oxygen species biosynthetic process / transport vesicle / positive regulation of protein autophosphorylation / Insulin receptor recycling / insulin-like growth factor receptor binding / neuron projection maintenance / positive regulation of protein metabolic process / NPAS4 regulates expression of target genes / positive regulation of brown fat cell differentiation / activation of protein kinase B activity / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of glycolytic process / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / positive regulation of nitric-oxide synthase activity / proteolysis involved in protein catabolic process / positive regulation of cytokine production / positive regulation of long-term synaptic potentiation / acute-phase response / endosome lumen / positive regulation of D-glucose import / Regulation of insulin secretion / negative regulation of proteolysis / positive regulation of protein secretion / positive regulation of cell differentiation / Peroxisomal protein import / regulation of transmembrane transporter activity / insulin receptor binding / peptide binding / wound healing / protein catabolic process / negative regulation of protein catabolic process / regulation of synaptic plasticity / hormone activity / antigen processing and presentation of endogenous peptide antigen via MHC class I / metalloendopeptidase activity / positive regulation of neuron projection development / cognition / positive regulation of protein localization to nucleus / Golgi lumen / vasodilation / positive regulation of protein catabolic process / glucose metabolic process / peroxisome / positive regulation of protein binding / insulin receptor signaling pathway / cell-cell signaling / glucose homeostasis / regulation of protein localization / positive regulation of NF-kappaB transcription factor activity / virus receptor activity / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / basolateral plasma membrane / protease binding / secretory granule lumen
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 / Insulinase (Peptidase family M16) ...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 / 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
Insulin / Insulin-degrading enzyme
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsMancl, J.M. / Liang, W.G. / Tang, W.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
CitationJournal: To be published
Title: Ensemble cryoEM reveals a substrate-induced shift in the conformational dynamics of human insulin degrading enzyme
Authors: Mancl, J.M. / Liang, W.G. / Wei, H. / Carragher, B. / Potter, C.S. / Tang, W.J.
History
DepositionAug 27, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 31, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 9, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cysteine-free Insulin-degrading enzyme
B: Cysteine-free Insulin-degrading enzyme
a: Insulin A chain
b: Insulin B chain


Theoretical massNumber of molelcules
Total (without water)239,9394
Polymers239,9394
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area4720 Å2
ΔGint-14 kcal/mol
Surface area83510 Å2

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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
Mutation: C110L, C171S, C178A, 257V, C414L, C573N, C590S, C789S, C812A, C819A, C904S, C966S, C974S
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
#2: Protein/peptide Insulin A chain


Mass: 2383.698 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INS / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: P01308
#3: Protein/peptide Insulin B chain


Mass: 3417.931 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INS / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: P01308
Has protein modificationY

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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

Component
IDNameTypeEntity IDParent-IDSource
1Cysteine-free Insulin-degrading enzyme in complex with Insulin A chain and Insulin B chainCOMPLEXall0RECOMBINANT
2Cysteine-free Insulin-degrading enzymeCOMPLEX#11RECOMBINANT
3Insulin A chain, Insulin B chainCOMPLEX#2-#31RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Escherichia coli (E. coli)562
23Saccharomyces cerevisiae (brewer's yeast)4932
Buffer solutionpH: 7.2
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 304011 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00816003
ELECTRON MICROSCOPYf_angle_d1.19521643
ELECTRON MICROSCOPYf_dihedral_angle_d17.1742078
ELECTRON MICROSCOPYf_chiral_restr0.0652334
ELECTRON MICROSCOPYf_plane_restr0.0092797

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