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- PDB-2wc0: crystal structure of human insulin degrading enzyme in complex wi... -

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Basic information

Entry
Database: PDB / ID: 2wc0
Titlecrystal structure of human insulin degrading enzyme in complex with iodinated insulin
Components
  • INSULIN A CHAIN
  • INSULIN B CHAIN
  • INSULIN-DEGRADING ENZYME
KeywordsHYDROLASE/HORMONE / ZINC / DIOXANE / INSULIN / HORMONE / PROTEASE / SECRETED / HUMAN INSULIN-DEGRADING ENZYME / DISULFIDE BOND / METALLOPROTEASE / GLUCOSE METABOLISM / CARBOHYDRATE METABOLISM / HYDROLASE / CYTOPLASM / POLYMORPHISM / METAL-BINDING / CLEAVAGE ON PAIR OF BASIC RESIDUES / HYDROLASE-HORMONE 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 / insulin binding / negative regulation of NAD(P)H oxidase activity / regulation of aerobic respiration ...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 / 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 / peptide catabolic process / Signaling by Insulin receptor / negative regulation of feeding behavior / IRS activation / regulation of protein secretion / Insulin processing / positive regulation of peptide hormone secretion / positive regulation of respiratory burst / amyloid-beta clearance / Regulation of gene expression in beta cells / negative regulation of acute inflammatory response / peroxisomal matrix / positive regulation of protein autophosphorylation / 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 / negative regulation of protein secretion / negative regulation of gluconeogenesis / positive regulation of glycogen biosynthetic process / Signal attenuation / fatty acid homeostasis / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / positive regulation of insulin receptor signaling pathway / negative regulation of lipid catabolic process / regulation of protein localization to plasma membrane / positive regulation of lipid biosynthetic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / activation of protein kinase B activity / COPI-mediated anterograde transport / transport vesicle / nitric oxide-cGMP-mediated signaling / negative regulation of reactive oxygen species biosynthetic process / Insulin receptor recycling / insulin-like growth factor receptor binding / positive regulation of brown fat cell differentiation / NPAS4 regulates expression of target genes / neuron projection maintenance / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of nitric-oxide synthase activity / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / regulation of transmembrane transporter activity / peptide binding / proteolysis involved in protein catabolic process / positive regulation of glycolytic process / positive regulation of long-term synaptic potentiation / positive regulation of cytokine production / acute-phase response / endosome lumen / positive regulation of protein secretion / positive regulation of D-glucose import / positive regulation of cell differentiation / Regulation of insulin secretion / insulin receptor binding / Peroxisomal protein import / wound healing / protein catabolic process / negative regulation of protein catabolic process / antigen processing and presentation of endogenous peptide antigen via MHC class I / hormone activity / regulation of synaptic plasticity / positive regulation of neuron projection development / metalloendopeptidase activity / positive regulation of protein localization to nucleus / Golgi lumen / cognition / glucose metabolic process / positive regulation of protein catabolic process / positive regulation of protein binding / vasodilation / peroxisome / insulin receptor signaling pathway / glucose homeostasis / cell-cell signaling / regulation of protein localization / virus receptor activity / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protease binding / positive regulation of cell growth / basolateral plasma membrane / secretory granule lumen / endopeptidase activity / positive regulation of canonical NF-kappaB signal transduction / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of MAPK cascade
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
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsManolopoulou, M. / Guo, Q. / Malito, E. / Schilling, A.B. / Tang, W.J.
CitationJournal: J.Biol.Chem. / Year: 2009
Title: Molecular Basis of Catalytic Chamber-Assisted Unfolding and Cleavage of Human Insulin by Human Insulin Degrading Enzyme.
Authors: Manolopoulou, M. / Guo, Q. / Malito, E. / Schilling, A.B. / Tang, W.J.
History
DepositionMar 6, 2009Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 24, 2009Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _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_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification
Remark 700 SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN ... SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN THE SHEET RECORDS BELOW, TWO SHEETS ARE DEFINED.

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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 A CHAIN
D: INSULIN B CHAIN
E: INSULIN A CHAIN
F: INSULIN B CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)241,59216
Polymers240,7566
Non-polymers83610
Water6,485360
1
A: INSULIN-DEGRADING ENZYME
C: INSULIN A CHAIN
D: INSULIN B CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)120,7968
Polymers120,3783
Non-polymers4185
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5490 Å2
ΔGint-53.84 kcal/mol
Surface area38280 Å2
MethodPISA
2
B: INSULIN-DEGRADING ENZYME
E: INSULIN A CHAIN
F: INSULIN B CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)120,7968
Polymers120,3783
Non-polymers4185
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5740 Å2
ΔGint-47.96 kcal/mol
Surface area38270 Å2
MethodPISA
Unit cell
Length a, b, c (Å)263.169, 263.169, 90.875
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number170
Space group name H-MP65

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein INSULIN-DEGRADING ENZYME / INSULIN PROTEASE / INSULYSIN / INSULINASE


Mass: 114560.578 Da / Num. of mol.: 2 / Fragment: RESIDUES 42-1019 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P14735, insulysin

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Protein/peptide , 2 types, 4 molecules CEDF

#2: Protein/peptide INSULIN A CHAIN


Mass: 2383.698 Da / Num. of mol.: 2 / Fragment: RESIDUES 90-110 / Source method: obtained synthetically / Source: (synth.) HOMO SAPIENS (human) / References: UniProt: P01308
#3: Protein/peptide INSULIN B CHAIN


Mass: 3433.953 Da / Num. of mol.: 2 / Fragment: RESIDUES 25-54 / Source method: obtained synthetically / Source: (synth.) HOMO SAPIENS (human) / References: UniProt: P01308

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Non-polymers , 3 types, 370 molecules

#4: Chemical ChemComp-ZN / ZINC ION


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


Mass: 88.105 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C4H8O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 360 / Source method: isolated from a natural source / Formula: H2O

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Details

Compound detailsENGINEERED RESIDUE IN CHAIN A, CYS 110 TO LEU ENGINEERED RESIDUE IN CHAIN A, GLU 111 TO GLN ...ENGINEERED RESIDUE IN CHAIN A, CYS 110 TO LEU ENGINEERED RESIDUE IN CHAIN A, GLU 111 TO GLN ENGINEERED RESIDUE IN CHAIN A, CYS 171 TO SER ENGINEERED RESIDUE IN CHAIN A, CYS 178 TO ALA ENGINEERED RESIDUE IN CHAIN A, CYS 257 TO VAL ENGINEERED RESIDUE IN CHAIN A, CYS 414 TO LEU ENGINEERED RESIDUE IN CHAIN A, CYS 573 TO ASN ENGINEERED RESIDUE IN CHAIN A, CYS 590 TO SER ENGINEERED RESIDUE IN CHAIN A, CYS 789 TO SER ENGINEERED RESIDUE IN CHAIN A, CYS 812 TO ALA ENGINEERED RESIDUE IN CHAIN A, CYS 819 TO ALA ENGINEERED RESIDUE IN CHAIN A, CYS 904 TO SER ENGINEERED RESIDUE IN CHAIN A, CYS 966 TO ASN ENGINEERED RESIDUE IN CHAIN A, CYS 974 TO ALA ENGINEERED RESIDUE IN CHAIN B, CYS 110 TO LEU ENGINEERED RESIDUE IN CHAIN B, GLU 111 TO GLN ENGINEERED RESIDUE IN CHAIN B, CYS 171 TO SER ENGINEERED RESIDUE IN CHAIN B, CYS 178 TO ALA ENGINEERED RESIDUE IN CHAIN B, CYS 257 TO VAL ENGINEERED RESIDUE IN CHAIN B, CYS 414 TO LEU ENGINEERED RESIDUE IN CHAIN B, CYS 573 TO ASN ENGINEERED RESIDUE IN CHAIN B, CYS 590 TO SER ENGINEERED RESIDUE IN CHAIN B, CYS 789 TO SER ENGINEERED RESIDUE IN CHAIN B, CYS 812 TO ALA ENGINEERED RESIDUE IN CHAIN B, CYS 819 TO ALA ENGINEERED RESIDUE IN CHAIN B, CYS 904 TO SER ENGINEERED RESIDUE IN CHAIN B, CYS 966 TO ASN ENGINEERED RESIDUE IN CHAIN B, CYS 974 TO ALA
Has protein modificationY

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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: 3.87 Å3/Da / Density % sol: 67.93 % / Description: NONE
Crystal growpH: 7 / Details: pH 7

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Data collection

DiffractionMean temperature: 287 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 1.548
DetectorType: ADSC CCD / Detector: CCD / Date: Apr 9, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.548 Å / Relative weight: 1
ReflectionResolution: 2.8→50 Å / Num. obs: 97980 / % possible obs: 99.6 % / Observed criterion σ(I): 2 / Redundancy: 6.5 % / Rmerge(I) obs: 0.13 / Net I/σ(I): 19.8
Reflection shellResolution: 2.8→2.91 Å / Redundancy: 5.2 % / Rmerge(I) obs: 0.53 / Mean I/σ(I) obs: 3.6 / % possible all: 98.3

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
HKL-3000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2G47

2g47


Resolution: 2.8→29.85 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.918 / SU B: 9.117 / SU ML: 0.182 / Cross valid method: THROUGHOUT / ESU R: 0.471 / ESU R Free: 0.279 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22 4422 5 %RANDOM
Rwork0.17 ---
obs0.172 83937 99.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 40.55 Å2
Baniso -1Baniso -2Baniso -3
1-0.02 Å20.01 Å20 Å2
2--0.02 Å20 Å2
3----0.03 Å2
Refinement stepCycle: LAST / Resolution: 2.8→29.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms16187 0 50 360 16597
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.030.02216636
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.5151.96822493
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.87151976
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.5524.573820
X-RAY DIFFRACTIONr_dihedral_angle_3_deg21.285152958
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.7141581
X-RAY DIFFRACTIONr_chiral_restr0.1550.22424
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0212625
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2640.28298
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3390.211419
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2030.2772
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.280.249
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2160.214
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.2851.510226
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.092216068
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.68837297
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it5.8574.56425
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.8→2.87 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.344 316 -
Rwork0.262 6071 -
obs--98.96 %

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