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- PDB-2g56: crystal structure of human insulin-degrading enzyme in complex wi... -

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Basic information

Entry
Database: PDB / ID: 2g56
Titlecrystal structure of human insulin-degrading enzyme in complex with insulin B chain
Components
  • Insulin
  • Insulin-degrading enzyme
KeywordsHYDROLASE / protein-peptide complex
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 / insulin 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 / insulin binding / regulation of aerobic respiration / 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 / peptide catabolic process / IRS activation / regulation of protein secretion / Insulin processing / positive regulation of peptide hormone secretion / positive regulation of respiratory burst / amyloid-beta clearance / negative regulation of acute inflammatory response / Regulation of gene expression in beta cells / peroxisomal matrix / alpha-beta T cell activation / positive regulation of dendritic spine maintenance / Synthesis, secretion, and deacylation of Ghrelin / negative regulation of respiratory burst involved in inflammatory response / amyloid-beta metabolic process / activation of protein kinase B activity / negative regulation of protein secretion / negative regulation of gluconeogenesis / positive regulation of insulin receptor signaling pathway / positive regulation of glycogen biosynthetic process / fatty acid homeostasis / Signal attenuation / positive regulation of protein binding / 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 / insulin-like growth factor receptor binding / positive regulation of brown fat cell differentiation / NPAS4 regulates expression of target genes / negative regulation of proteolysis / neuron projection maintenance / endoplasmic reticulum-Golgi intermediate compartment membrane / peptide binding / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / proteolysis involved in protein catabolic process / 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 D-glucose import / positive regulation of protein secretion / insulin receptor binding / positive regulation of cell differentiation / Regulation of insulin secretion / Peroxisomal protein import / protein catabolic process / wound healing / positive regulation of neuron projection development / hormone activity / antigen processing and presentation of endogenous peptide antigen via MHC class I / negative regulation of protein catabolic process / regulation of synaptic plasticity / metalloendopeptidase activity / positive regulation of protein localization to nucleus / Golgi lumen / vasodilation / cognition / glucose metabolic process / positive regulation of protein catabolic process / insulin receptor signaling pathway / peroxisome / cell-cell signaling / glucose homeostasis / regulation of protein localization / amyloid-beta binding / virus receptor activity / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / protease binding / secretory granule lumen / endopeptidase activity / basolateral plasma membrane / positive regulation of canonical NF-kappaB signal transduction / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
Similarity search - Function
Peptidase M16, middle/third domain / Middle or third domain of peptidase_M16 / : / PQQ synthase PqqF-like, C-terminal lobe domain 4 / : / Cytochrome Bc1 Complex; Chain A, domain 1 / Metalloenzyme, LuxS/M16 peptidase-like / Peptidase M16, zinc-binding site / Insulinase family, zinc-binding region signature. / Peptidase M16, C-terminal ...Peptidase M16, middle/third domain / Middle or third domain of peptidase_M16 / : / PQQ synthase PqqF-like, C-terminal lobe domain 4 / : / Cytochrome Bc1 Complex; Chain A, domain 1 / Metalloenzyme, LuxS/M16 peptidase-like / 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 / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
1,4-DIETHYLENE DIOXIDE / Insulin / Insulin-degrading enzyme / Insulin-degrading enzyme
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsShen, Y. / Tang, W.-J.
CitationJournal: Nature / Year: 2006
Title: Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism.
Authors: Shen, Y. / Joachimiak, A. / Rosner, M.R. / Tang, W.J.
History
DepositionFeb 22, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 24, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 20, 2021Group: Database references / Derived calculations / Category: database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Aug 30, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Insulin-degrading enzyme
B: Insulin-degrading enzyme
C: Insulin
D: Insulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)236,3865
Polymers236,2984
Non-polymers881
Water18,8081044
1
A: Insulin-degrading enzyme
C: Insulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)118,2373
Polymers118,1492
Non-polymers881
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2330 Å2
ΔGint-6 kcal/mol
Surface area38440 Å2
MethodPISA
2
B: Insulin-degrading enzyme
D: Insulin


Theoretical massNumber of molelcules
Total (without water)118,1492
Polymers118,1492
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2130 Å2
ΔGint-12 kcal/mol
Surface area38370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)262.250, 262.250, 90.610
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number170
Space group name H-MP65
Detailsthe biological assembly is a monomer.

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Components

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


Mass: 114715.141 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IDE / Plasmid: pProEx / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta(DE3)
References: UniProt: Q5T5N2, UniProt: P14735*PLUS, insulysin
#2: Protein/peptide Insulin


Mass: 3433.953 Da / Num. of mol.: 2 / Fragment: Insulin B chain, residues 25-54 / Source method: obtained synthetically
Details: This sequence occurs naturally in Homo sapiens (Humans)
References: UniProt: P01308
#3: Chemical ChemComp-DIO / 1,4-DIETHYLENE DIOXIDE


Mass: 88.105 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H8O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1044 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.8 Å3/Da / Density % sol: 67.67 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7
Details: PEGMME5000, dioxane, tacismate, hepes, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.9 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Aug 23, 2005
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9 Å / Relative weight: 1
ReflectionResolution: 2.2→30 Å / Num. all: 175528 / Num. obs: 175528 / % possible obs: 99 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 8.4 % / Biso Wilson estimate: 20.7 Å2 / Rsym value: 0.064 / Net I/σ(I): 26.5
Reflection shellResolution: 2.2→2.28 Å / Redundancy: 5.7 % / Mean I/σ(I) obs: 4.6 / Num. unique all: 15806 / Rsym value: 0.347 / % possible all: 87.9

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Processing

Software
NameVersionClassification
CNS1.1refinement
HKL-2000data reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2G54

2g54


Resolution: 2.2→29.75 Å / Rfactor Rfree error: 0.002 / Data cutoff high absF: 142221.1 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.225 16995 9.9 %RANDOM
Rwork0.205 ---
obs0.205 171194 95.1 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 51.0152 Å2 / ksol: 0.3739 e/Å3
Displacement parametersBiso mean: 32.2 Å2
Baniso -1Baniso -2Baniso -3
1--1.3 Å22.15 Å20 Å2
2---1.3 Å20 Å2
3---2.6 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.28 Å0.25 Å
Luzzati d res low-5 Å
Luzzati sigma a0.24 Å0.21 Å
Refinement stepCycle: LAST / Resolution: 2.2→29.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15914 0 6 1044 16964
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.009
X-RAY DIFFRACTIONc_angle_deg1.3
X-RAY DIFFRACTIONc_dihedral_angle_d23.1
X-RAY DIFFRACTIONc_improper_angle_d0.88
X-RAY DIFFRACTIONc_mcbond_it1.161.5
X-RAY DIFFRACTIONc_mcangle_it1.742
X-RAY DIFFRACTIONc_scbond_it2.182
X-RAY DIFFRACTIONc_scangle_it3.252.5
LS refinement shellResolution: 2.2→2.34 Å / Rfactor Rfree error: 0.005 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.259 2480 10 %
Rwork0.238 22242 -
obs--82.9 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2water_rep.paramwater.top
X-RAY DIFFRACTION3dox.pardox.top

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