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- PDB-3e50: Crystal structure of human insulin degrading enzyme in complex wi... -

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Basic information

Entry
Database: PDB / ID: 3.0E+50
TitleCrystal structure of human insulin degrading enzyme in complex with transforming growth factor-alpha
Components
  • Insulin-degrading enzyme
  • Protransforming growth factor alpha
KeywordsHydrolase/Hormone / IDE / TGF-ALPHA / Cytoplasm / Hydrolase / Metal-binding / Metalloprotease / Polymorphism / Protease / Zinc / Cell membrane / EGF-like domain / Glycoprotein / Growth factor / Lipoprotein / Membrane / Mitogen / Palmitate / Secreted / Transmembrane / Hydrolase-Hormone COMPLEX
Function / homology
Function and homology information


insulysin / hepatocyte proliferation / ubiquitin recycling / insulin catabolic process / insulin metabolic process / amyloid-beta clearance by cellular catabolic process / hormone catabolic process / bradykinin catabolic process / Cargo concentration in the ER / ubiquitin-modified protein reader activity ...insulysin / hepatocyte proliferation / ubiquitin recycling / insulin catabolic process / insulin metabolic process / amyloid-beta clearance by cellular catabolic process / hormone catabolic process / bradykinin catabolic process / Cargo concentration in the ER / ubiquitin-modified protein reader activity / Inhibition of Signaling by Overexpressed EGFR / COPII-mediated vesicle transport / EGFR interacts with phospholipase C-gamma / insulin binding / ERBB2-EGFR signaling pathway / regulation of aerobic respiration / epidermal growth factor receptor binding / Signaling by EGFR / peptide catabolic process / transmembrane receptor protein tyrosine kinase activator activity / amyloid-beta clearance / peroxisomal matrix / positive regulation of cell division / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / mammary gland alveolus development / GAB1 signalosome / amyloid-beta metabolic process / GRB2 events in EGFR signaling / Insulin receptor recycling / SHC1 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / endoplasmic reticulum-Golgi intermediate compartment membrane / proteolysis involved in protein catabolic process / positive regulation of mitotic nuclear division / positive regulation of epithelial cell proliferation / Peroxisomal protein import / peptide binding / EGFR downregulation / clathrin-coated endocytic vesicle membrane / protein catabolic process / growth factor activity / epidermal growth factor receptor signaling pathway / ER to Golgi transport vesicle membrane / metalloendopeptidase activity / antigen processing and presentation of endogenous peptide antigen via MHC class I / peroxisome / positive regulation of protein catabolic process / Constitutive Signaling by Aberrant PI3K in Cancer / positive regulation of peptidyl-tyrosine phosphorylation / Cargo recognition for clathrin-mediated endocytosis / virus receptor activity / PIP3 activates AKT signaling / insulin receptor signaling pathway / Clathrin-mediated endocytosis / positive regulation of protein binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / cytoplasmic vesicle / RAF/MAP kinase cascade / basolateral plasma membrane / angiogenesis / endopeptidase activity / Estrogen-dependent gene expression / Extra-nuclear estrogen signaling / positive regulation of MAPK cascade / receptor ligand activity / Ub-specific processing proteases / intracellular signal transduction / external side of plasma membrane / positive regulation of cell population proliferation / endoplasmic reticulum membrane / perinuclear region of cytoplasm / cell surface / protein homodimerization activity / mitochondrion / proteolysis / extracellular space / extracellular exosome / zinc ion binding / extracellular region / ATP binding / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
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 / EGF-like domain profile. / EGF-like domain signature 2. / EGF-like domain signature 1. / EGF-like domain / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Protransforming growth factor alpha / Insulin-degrading enzyme
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsGuo, Q. / Manolopoulou, M. / Tang, W.-J.
CitationJournal: J.Mol.Biol. / Year: 2010
Title: Molecular Basis for the Recognition and Cleavages of IGF-II, TGF-alpha, and Amylin by Human Insulin-Degrading Enzyme.
Authors: Guo, Q. / Manolopoulou, M. / Bian, Y. / Schilling, A.B. / Tang, W.J.
History
DepositionAug 12, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 18, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 20, 2021Group: Database references / Derived calculations
Category: database_2 / pdbx_struct_conn_angle ...database_2 / pdbx_struct_conn_angle / 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 / _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_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_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 1.3Feb 21, 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: Protransforming growth factor alpha
D: Protransforming growth factor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)240,6826
Polymers240,5514
Non-polymers1312
Water10,233568
1
A: Insulin-degrading enzyme
C: Protransforming growth factor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)120,3413
Polymers120,2752
Non-polymers651
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area660 Å2
ΔGint-37 kcal/mol
Surface area38130 Å2
MethodPISA
2
B: Insulin-degrading enzyme
D: Protransforming growth factor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)120,3413
Polymers120,2752
Non-polymers651
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2000 Å2
ΔGint-44 kcal/mol
Surface area38060 Å2
MethodPISA
Unit cell
Length a, b, c (Å)262.172, 262.172, 90.522
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 / Insulinase / Insulysin


Mass: 114715.141 Da / Num. of mol.: 2 / Fragment: UNP residues 42-1019 / Mutation: E111Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: hCG_1810909, IDE, RP11-366I13.1-001 / Production host: Escherichia coli (E. coli) / References: UniProt: P14735, insulysin
#2: Protein/peptide Protransforming growth factor alpha / Transforming growth factor alpha / TGF-alpha / EGF-like TGF / ETGF / TGF type 1


Mass: 5560.246 Da / Num. of mol.: 2
Fragment: UNP residues 40-89, Transforming growth factor alpha chain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TGFA / References: UniProt: P01135
#3: Chemical ChemComp-ZN / ZINC ION


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


Mass: 18.015 Da / Num. of mol.: 568 / 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: 3.73 Å3/Da / Density % sol: 67.05 %

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Data collection

DiffractionMean temperature: 298 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 1.0003 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Jun 28, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0003 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. all: 159824 / Num. obs: 157230 / % possible obs: 100 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 7.1 % / Biso Wilson estimate: 11.9 Å2 / Rmerge(I) obs: 0.094 / Rsym value: 0.087 / Net I/σ(I): 23.6

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Processing

SoftwareName: REFMAC / Version: 5.2.0019 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→50 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.924 / SU B: 4.982 / SU ML: 0.123 / Cross valid method: THROUGHOUT / ESU R: 0.196 / ESU R Free: 0.179 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23133 7893 5 %RANDOM
Rwork0.1907 ---
obs0.19274 149322 99.79 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 32.94 Å2
Baniso -1Baniso -2Baniso -3
1--0.05 Å2-0.03 Å2-0 Å2
2---0.05 Å20 Å2
3---0.08 Å2
Refinement stepCycle: LAST / Resolution: 2.3→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15727 0 2 568 16297
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0240.02216102
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.9821.96521775
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.88751920
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.05524.503795
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.014152872
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.1781582
X-RAY DIFFRACTIONr_chiral_restr0.150.22349
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0212250
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2220.27327
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3120.210869
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1610.2765
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1960.256
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2470.215
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.231.510002
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.989215629
X-RAY DIFFRACTIONr_scbond_it3.42936977
X-RAY DIFFRACTIONr_scangle_it5.0384.56146
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.282 583 -
Rwork0.23 10985 -
obs--99.81 %

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