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- PDB-4gsc: Structure analysis of insulin degrading enzyme with compound bdm4... -

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Basic information

Entry
Database: PDB / ID: 4gsc
TitleStructure analysis of insulin degrading enzyme with compound bdm41559 ((s)-2-[2-(carboxymethyl-phenethyl-amino)-acetylamino]-3-(1h-imidazol-4-yl)-propionic acid methyl ester)
ComponentsInsulin-degrading enzyme
KeywordsHYDROLASE/HYDROLASE INHIBITOR / INSULIN DEGRADING ENZYME / HYDROLASE-HYDROLASE INHIBITOR 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 / 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 / ubiquitin-modified protein reader activity / insulin binding / regulation of aerobic respiration / peptide catabolic process / amyloid-beta clearance / peroxisomal matrix / amyloid-beta metabolic process / Insulin receptor recycling / proteolysis involved in protein catabolic process / Peroxisomal protein import / peptide binding / protein catabolic process / antigen processing and presentation of endogenous peptide antigen via MHC class I / metalloendopeptidase activity / positive regulation of protein catabolic process / peroxisome / positive regulation of protein binding / insulin receptor signaling pathway / virus receptor activity / basolateral plasma membrane / endopeptidase activity / Ub-specific processing proteases / external side of plasma membrane / cell surface / protein homodimerization activity / mitochondrion / proteolysis / extracellular space / zinc ion binding / extracellular exosome / ATP binding / identical protein binding / nucleus / cytoplasm / cytosol
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 / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-MGW / Insulin-degrading enzyme
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.81 Å
AuthorsGuo, Q. / Deprez-Poulain, R. / Deprez, B. / Tang, W.J.
CitationJournal: Eur.J.Med.Chem. / Year: 2014
Title: Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, substrate-dependent modulators of insulin-degrading enzyme in amyloid-beta hydrolysis.
Authors: Charton, J. / Gauriot, M. / Guo, Q. / Hennuyer, N. / Marechal, X. / Dumont, J. / Hamdane, M. / Pottiez, V. / Landry, V. / Sperandio, O. / Flipo, M. / Buee, L. / Staels, B. / Leroux, F. / ...Authors: Charton, J. / Gauriot, M. / Guo, Q. / Hennuyer, N. / Marechal, X. / Dumont, J. / Hamdane, M. / Pottiez, V. / Landry, V. / Sperandio, O. / Flipo, M. / Buee, L. / Staels, B. / Leroux, F. / Tang, W.J. / Deprez, B. / Deprez-Poulain, R.
History
DepositionAug 27, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 28, 2013Provider: repository / Type: Initial release
Revision 1.1Apr 16, 2014Group: Database references
Revision 1.2May 28, 2014Group: Database references
Revision 1.3Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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_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.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_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_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_label_asym_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)230,0296
Polymers229,1212
Non-polymers9084
Water3,243180
1
A: Insulin-degrading enzyme
hetero molecules


Theoretical massNumber of molelcules
Total (without water)115,0143
Polymers114,5611
Non-polymers4542
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Insulin-degrading enzyme
hetero molecules


Theoretical massNumber of molelcules
Total (without water)115,0143
Polymers114,5611
Non-polymers4542
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)263.759, 263.759, 91.260
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 / Abeta-degrading protease / Insulin protease / Insulinase / Insulysin


Mass: 114560.578 Da / Num. of mol.: 2 / Fragment: UNP RESIDUES 42-1019
Mutation: C110L,E111Q,C171S,C178A,C257V,C414L,C573N,C590S,C789S,C812A,C819A,C904S,C966N,C974A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IDE / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P14735, insulysin
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-MGW / methyl N-(carboxymethyl)-N-(2-phenylethyl)glycyl-L-histidinate / ( (S)-2-[2-(Carboxymethyl-phenethyl-amino)-acetylamino]-3-(1H-imidazol-4-yl)-propionic acid methyl ester


Mass: 388.418 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H24N4O5
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 180 / 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: 4 Å3/Da / Density % sol: 69.25 %
Crystal growMethod: vapor diffusion, hanging drop / pH: 7
Details: 10-13% PEG MME 5000, 100 MM HEPES PH 7.0, 4-14% TACSIMATE, 10% DIOXANE, VAPOR DIFFUSION, HANGING DROP, TEMPERATURE 287K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.9597
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Feb 19, 2010
RadiationMonochromator: MAR 345 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9597 Å / Relative weight: 1
ReflectionResolution: 2.81→50 Å / Num. all: 79021 / Num. obs: 75029 / % possible obs: 100 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 2
Reflection shellResolution: 2.81→2.9 Å / % possible all: 100

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Processing

Software
NameVersionClassification
HKL-3000data collection
PHASESphasing
REFMAC5.5.0102refinement
HKL-3000data reduction
HKL-3000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2WBY

2wby


Resolution: 2.81→49.85 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.89 / SU B: 12.381 / SU ML: 0.242 / Cross valid method: THROUGHOUT / σ(F): 1 / ESU R: 0.677 / ESU R Free: 0.345 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.253 3992 5.1 %RANDOM
Rwork0.195 ---
all0.257 79021 --
obs0.198 75029 89.4 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 45.65 Å2
Baniso -1Baniso -2Baniso -3
1-0.09 Å20.05 Å2-0 Å2
2--0.09 Å2-0 Å2
3----0.14 Å2
Refinement stepCycle: LAST / Resolution: 2.81→49.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15620 0 58 180 15858
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.02216068
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.8751.96921735
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg751908
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.62624.516795
X-RAY DIFFRACTIONr_dihedral_angle_3_deg21.849152868
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.1811582
X-RAY DIFFRACTIONr_chiral_restr0.1230.22334
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.02112262
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.7061.59574
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.44215494
X-RAY DIFFRACTIONr_scbond_it2.34136494
X-RAY DIFFRACTIONr_scangle_it4.0994.56241
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.81→2.88 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.326 196 -
Rwork0.282 3771 -
obs--61.17 %

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