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- PDB-2g54: Crystal structure of Zn-bound human insulin-degrading enzyme in c... -

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Basic information

Entry
Database: PDB / ID: 2g54
TitleCrystal structure of Zn-bound human insulin-degrading enzyme in complex with insulin B chain
Components
  • Insulin-degrading enzyme
  • insulin
KeywordsHYDROLASE / protein-peptide complex
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 / ubiquitin-modified protein reader activity / insulin binding / negative regulation of NAD(P)H oxidase activity ...insulysin / ubiquitin recycling / insulin catabolic process / insulin metabolic process / amyloid-beta clearance by cellular catabolic process / hormone catabolic process / bradykinin catabolic process / ubiquitin-modified protein reader activity / insulin binding / negative regulation of NAD(P)H oxidase activity / regulation of aerobic respiration / negative regulation of glycogen catabolic process / regulation of cellular amino acid metabolic process / peptide catabolic process / Signaling by Insulin receptor / IRS activation / nitric oxide-cGMP-mediated signaling / negative regulation of fatty acid metabolic process / Insulin processing / negative regulation of feeding behavior / regulation of protein secretion / amyloid-beta clearance / positive regulation of peptide hormone secretion / Regulation of gene expression in beta cells / positive regulation of respiratory burst / peroxisomal matrix / positive regulation of dendritic spine maintenance / alpha-beta T cell activation / negative regulation of acute inflammatory response / negative regulation of respiratory burst involved in inflammatory response / negative regulation of protein secretion / fatty acid homeostasis / Synthesis, secretion, and deacylation of Ghrelin / positive regulation of glycogen biosynthetic process / positive regulation of lipid biosynthetic process / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / negative regulation of gluconeogenesis / positive regulation of nitric oxide mediated signal transduction / regulation of protein localization to plasma membrane / COPI-mediated anterograde transport / amyloid-beta metabolic process / negative regulation of lipid catabolic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / positive regulation of insulin receptor signaling pathway / negative regulation of reactive oxygen species biosynthetic process / transport vesicle / positive regulation of protein autophosphorylation / Insulin receptor recycling / insulin-like growth factor receptor binding / NPAS4 regulates expression of target genes / positive regulation of protein metabolic process / neuron projection maintenance / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of brown fat cell differentiation / activation of protein kinase B activity / positive regulation of glycolytic process / proteolysis involved in protein catabolic process / Insulin receptor signalling cascade / positive regulation of mitotic nuclear division / Regulation of insulin secretion / positive regulation of nitric-oxide synthase activity / positive regulation of long-term synaptic potentiation / endosome lumen / positive regulation of cytokine production / acute-phase response / positive regulation of protein secretion / regulation of transmembrane transporter activity / Peroxisomal protein import / positive regulation of cell differentiation / positive regulation of glucose import / peptide binding / negative regulation of proteolysis / regulation of synaptic plasticity / protein catabolic process / wound healing / insulin receptor binding / negative regulation of protein catabolic process / positive regulation of neuron projection development / hormone activity / metalloendopeptidase activity / antigen processing and presentation of endogenous peptide antigen via MHC class I / cognition / peroxisome / Golgi lumen / vasodilation / positive regulation of protein localization to nucleus / positive regulation of protein catabolic process / glucose metabolic process / regulation of protein localization / glucose homeostasis / virus receptor activity / cell-cell signaling / insulin receptor signaling pathway / positive regulation of NF-kappaB transcription factor activity / positive regulation of protein binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / basolateral plasma membrane / secretory granule lumen
Similarity search - Function
Peptidase M16, middle/third domain / Middle or third domain of peptidase_M16 / 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) ...Peptidase M16, middle/third domain / Middle or third domain of peptidase_M16 / 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/IGF/Relaxin family / Insulin, conserved site / Insulin family signature. / Insulin-like / Insulin / insulin-like growth factor / relaxin family. / 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 / SAD / Resolution: 2.25 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_conn ...database_2 / struct_conn / 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_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Feb 14, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)236,6058
Polymers236,2984
Non-polymers3074
Water14,178787
1
A: Insulin-degrading enzyme
C: insulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)118,3034
Polymers118,1492
Non-polymers1542
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2380 Å2
ΔGint-46 kcal/mol
Surface area38390 Å2
MethodPISA
2
B: Insulin-degrading enzyme
D: insulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)118,3034
Polymers118,1492
Non-polymers1542
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2420 Å2
ΔGint-45 kcal/mol
Surface area38190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)262.528, 262.528, 90.503
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 / Mutation: E111Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IDE / Production host: Escherichia coli (E. coli)
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-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-DIO / 1,4-DIETHYLENE DIOXIDE / 1,4-Dioxane


Mass: 88.105 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H8O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 787 / 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: 3.81 Å3/Da / Density % sol: 67.69 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7
Details: PEGMME5000, dioxane, HEPES buffer, tacismate, 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: 14-BM-C / Wavelength: 0.9 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Jun 20, 2005
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9 Å / Relative weight: 1
ReflectionResolution: 2.25→50 Å / Num. all: 166009 / Num. obs: 166009 / % possible obs: 99 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 10.5 % / Biso Wilson estimate: 29 Å2 / Rsym value: 0.086 / Net I/σ(I): 27.3
Reflection shellResolution: 2.25→2.33 Å / Redundancy: 7.1 % / Mean I/σ(I) obs: 2.6 / Rsym value: 0.638 / % possible all: 82.9

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Processing

Software
NameVersionClassification
CNS1.1refinement
HKL-2000data reduction
SCALEPACKdata scaling
SHARPphasing
RefinementMethod to determine structure: SAD / Resolution: 2.25→28.03 Å / Rfactor Rfree error: 0.002 / Data cutoff high absF: 142998.05 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.233 15987 10 %RANDOM
Rwork0.206 ---
obs0.206 160352 95.1 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 37.6467 Å2 / ksol: 0.367426 e/Å3
Displacement parametersBiso mean: 37.6 Å2
Baniso -1Baniso -2Baniso -3
1--1.22 Å23.02 Å20 Å2
2---1.22 Å20 Å2
3---2.45 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.31 Å0.26 Å
Luzzati d res low-5 Å
Luzzati sigma a0.29 Å0.27 Å
Refinement stepCycle: LAST / Resolution: 2.25→28.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15948 0 14 787 16749
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.3
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d22.9
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.87
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.231.5
X-RAY DIFFRACTIONc_mcangle_it1.832
X-RAY DIFFRACTIONc_scbond_it2.022
X-RAY DIFFRACTIONc_scangle_it2.952.5
LS refinement shellResolution: 2.25→2.39 Å / Rfactor Rfree error: 0.006 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.297 2216 9.9 %
Rwork0.266 20274 -
obs--80.4 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2water_rep.paramwater.top
X-RAY DIFFRACTION3dox.pardox.top
X-RAY DIFFRACTION4ion.paramion.top

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