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- PDB-2wby: Crystal structure of human insulin-degrading enzyme in complex wi... -

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Basic information

Entry
Database: PDB / ID: 2wby
TitleCrystal structure of human insulin-degrading enzyme in complex with insulin
Components
  • INSULIN A CHAIN
  • INSULIN B CHAIN
  • INSULIN-DEGRADING ENZYME
KeywordsHYDROLASE/HORMONE / GLUCOSE METABOLISM / CARBOHYDRATE METABOLISM / DISEASE MUTATION / DIABETES MELLITUS / ZINC / DIOXANE / INSULIN / HORMONE / SECRETED / PROTEASE / DISULFIDE BOND / PHARMACEUTICAL / METALLOPROTEASE / HUMAN INSULIN-DEGRADNG ENZYME / HYDROLASE / CYTOPLASM / POLYMORPHISM / METAL-BINDING / CLEAVAGE ON PAIR OF BASIC RESIDUES / HYDROLASE-HORMONE 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 / Signaling by Insulin receptor / negative regulation of feeding behavior / IRS activation / Insulin processing / peptide catabolic process / regulation of protein secretion / positive regulation of peptide hormone secretion / positive regulation of respiratory burst / Regulation of gene expression in beta cells / negative regulation of acute inflammatory response / peroxisomal matrix / amyloid-beta clearance / alpha-beta T cell activation / positive regulation of protein binding / Synthesis, secretion, and deacylation of Ghrelin / amyloid-beta metabolic process / positive regulation of dendritic spine maintenance / negative regulation of protein secretion / negative regulation of gluconeogenesis / positive regulation of glycogen biosynthetic process / fatty acid homeostasis / Signal attenuation / positive regulation of insulin receptor signaling pathway / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / negative regulation of respiratory burst involved in inflammatory response / 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 / transport vesicle / nitric oxide-cGMP-mediated signaling / positive regulation of nitric-oxide synthase activity / COPI-mediated anterograde transport / Insulin receptor recycling / negative regulation of reactive oxygen species biosynthetic process / positive regulation of brown fat cell differentiation / insulin-like growth factor receptor binding / negative regulation of proteolysis / NPAS4 regulates expression of target genes / neuron projection maintenance / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of mitotic nuclear division / peptide binding / Insulin receptor signalling cascade / : / positive regulation of glycolytic process / endosome lumen / positive regulation of cytokine production / acute-phase response / positive regulation of long-term synaptic potentiation / positive regulation of D-glucose import across plasma membrane / positive regulation of protein secretion / insulin receptor binding / protein catabolic process / positive regulation of cell differentiation / Peroxisomal protein import / Regulation of insulin secretion / wound healing / positive regulation of neuron projection development / hormone activity / antigen processing and presentation of endogenous peptide antigen via MHC class I / metalloendopeptidase activity / negative regulation of protein catabolic process / regulation of synaptic plasticity / 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 / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / virus receptor activity / 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 / 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
Insulin / Insulin-degrading enzyme
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 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_seq_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _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_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)238,0868
Polymers237,9556
Non-polymers1312
Water13,007722
1
A: INSULIN-DEGRADING ENZYME
C: INSULIN A CHAIN
D: INSULIN B CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)119,0434
Polymers118,9783
Non-polymers651
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4430 Å2
ΔGint-64.42 kcal/mol
Surface area38420 Å2
MethodPISA
2
B: INSULIN-DEGRADING ENZYME
E: INSULIN A CHAIN
F: INSULIN B CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)119,0434
Polymers118,9783
Non-polymers651
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4500 Å2
ΔGint-70.22 kcal/mol
Surface area38380 Å2
MethodPISA
Unit cell
Length a, b, c (Å)262.319, 262.319, 90.609
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number170
Space group name H-MP65

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Components

#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) / Strain (production host): BL21(DE3) PUBS520 / References: UniProt: P14735, insulysin
#2: Protein/peptide INSULIN A CHAIN


Mass: 2269.595 Da / Num. of mol.: 2 / Fragment: RESIDUES 90-109 / Source method: obtained synthetically / Source: (synth.) HOMO SAPIENS (human) / References: UniProt: P01308
#3: Protein/peptide INSULIN B CHAIN


Mass: 2147.518 Da / Num. of mol.: 2 / Fragment: RESIDUES 25-43 / Source method: obtained synthetically / Source: (synth.) HOMO SAPIENS (human) / References: UniProt: P01308
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 722 / Source method: isolated from a natural source / Formula: H2O
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: 3.8 Å3/Da / Density % sol: 67 % / Description: NONE
Crystal growpH: 7
Details: 10-13% PEG MME 5000, 100 MM HEPES PH 7.0, 4-14% TACSIMATE, 10% DIOXANE

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Data collection

DiffractionMean temperature: 287 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 14-BM-C / Wavelength: 0.9
DetectorDetector: CCD / Date: Jun 11, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. obs: 109017 / % possible obs: 99.9 % / Observed criterion σ(I): 1 / Redundancy: 7 % / Rmerge(I) obs: 0.13 / Net I/σ(I): 21
Reflection shellResolution: 2.6→2.69 Å / Redundancy: 6.5 % / Rmerge(I) obs: 0.52 / Mean I/σ(I) obs: 4.8 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2G47

2g47


Resolution: 2.6→32.08 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.914 / SU B: 6.876 / SU ML: 0.148 / Cross valid method: THROUGHOUT / ESU R: 0.299 / ESU R Free: 0.233 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.218 5438 5 %RANDOM
Rwork0.164 ---
obs0.167 103440 99.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 28.81 Å2
Baniso -1Baniso -2Baniso -3
1--0.02 Å2-0.01 Å2-0 Å2
2---0.02 Å20 Å2
3---0.03 Å2
Refinement stepCycle: LAST / Resolution: 2.6→32.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms16202 0 2 722 16926
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0240.02216604
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.1011.96622470
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.80951980
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.32424.573820
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.115152961
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.8921581
X-RAY DIFFRACTIONr_chiral_restr0.1390.22428
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0212641
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2420.28108
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3250.211409
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1690.2976
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.240.255
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2590.211
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.1151.510208
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.881216092
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.42137218
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it5.424.56378
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: 2.6→2.67 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.301 393 -
Rwork0.222 7559 -
obs--99.85 %

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