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- PDB-4re9: Crystal structure of human insulin degrading enzyme (IDE) in comp... -

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Basic information

Entry
Database: PDB / ID: 4re9
TitleCrystal structure of human insulin degrading enzyme (IDE) in complex with compound 71290
ComponentsInsulin-degrading enzyme
KeywordsHYDROLASE/HYDROLASE INHIBITOR / HYDROLASE-HYDROLASE INHIBITOR 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 / peptide catabolic process / amyloid-beta clearance / peroxisomal matrix / amyloid-beta metabolic process / positive regulation of protein binding / Insulin receptor recycling / negative regulation of proteolysis / peptide binding / proteolysis involved in protein catabolic process / Peroxisomal protein import / protein catabolic process / antigen processing and presentation of endogenous peptide antigen via MHC class I / metalloendopeptidase activity / positive regulation of protein catabolic process / insulin receptor signaling pathway / peroxisome / amyloid-beta binding / virus receptor activity / endopeptidase activity / basolateral plasma membrane / Ub-specific processing proteases / external side of plasma membrane / protein-containing complex binding / cell surface / protein homodimerization activity / ATP hydrolysis activity / mitochondrion / proteolysis / extracellular space / extracellular exosome / zinc ion binding / ATP binding / identical protein binding / nucleus / cytoplasm / cytosol
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 / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-3M9 / DI(HYDROXYETHYL)ETHER / Insulin-degrading enzyme
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.908 Å
AuthorsLiang, W.G. / Deprez, R. / Deprez, B. / Tang, W.J.
CitationJournal: Nat Commun / Year: 2015
Title: Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice.
Authors: Deprez-Poulain, R. / Hennuyer, N. / Bosc, D. / Liang, W.G. / Enee, E. / Marechal, X. / Charton, J. / Totobenazara, J. / Berte, G. / Jahklal, J. / Verdelet, T. / Dumont, J. / Dassonneville, S. ...Authors: Deprez-Poulain, R. / Hennuyer, N. / Bosc, D. / Liang, W.G. / Enee, E. / Marechal, X. / Charton, J. / Totobenazara, J. / Berte, G. / Jahklal, J. / Verdelet, T. / Dumont, J. / Dassonneville, S. / Woitrain, E. / Gauriot, M. / Paquet, C. / Duplan, I. / Hermant, P. / Cantrelle, F.X. / Sevin, E. / Culot, M. / Landry, V. / Herledan, A. / Piveteau, C. / Lippens, G. / Leroux, F. / Tang, W.J. / van Endert, P. / Staels, B. / Deprez, B.
History
DepositionSep 22, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 30, 2015Provider: repository / Type: Initial release
Revision 1.1Oct 28, 2015Group: Database references
Revision 1.2Sep 20, 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_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_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)232,22521
Polymers229,1232
Non-polymers3,10219
Water1,67593
1
A: Insulin-degrading enzyme
hetero molecules


Theoretical massNumber of molelcules
Total (without water)116,18811
Polymers114,5621
Non-polymers1,62610
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Insulin-degrading enzyme
hetero molecules


Theoretical massNumber of molelcules
Total (without water)116,03810
Polymers114,5621
Non-polymers1,4769
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)262.981, 262.981, 90.508
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 / Abeta-degrading protease / Insulin protease / Insulinase / Insulysin


Mass: 114561.562 Da / Num. of mol.: 2 / Fragment: UNP residues 42-1019
Mutation: C110L, 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

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Non-polymers , 7 types, 112 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-3M9 / 4-fluoro-N-({1-[(2R)-4-(hydroxyamino)-1-(naphthalen-2-yl)-4-oxobutan-2-yl]-1H-1,2,3-triazol-5-yl}methyl)benzamide


Mass: 447.462 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H22FN5O3
#4: Chemical ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES


Mass: 238.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#5: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C4H10O3
#6: Chemical ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400


Mass: 238.278 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H22O6 / Comment: precipitant*YM
#7: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 93 / 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: 3.97 Å3/Da / Density % sol: 68.99 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 10% PEG5000, 100 mM HEPES, 14% Tacsimate, 10% dioxane, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 291.15K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.9793 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD
RadiationMonochromator: Rosenbaum-Rock high-resolution double-crystal Si(111)
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.9→50 Å / Num. all: 78800 / Num. obs: 78721 / % possible obs: 99.9 % / Observed criterion σ(F): 2.1 / Observed criterion σ(I): 2.1 / Redundancy: 5.3 % / Rmerge(I) obs: 0.164 / Rsym value: 0.137 / Net I/σ(I): 11.4
Reflection shellResolution: 2.9→2.95 Å / Redundancy: 3.7 % / % possible all: 100

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Processing

Software
NameVersionClassification
HKL-3000data collection
PHASERphasing
PHENIX(phenix.refine: 1.9_1692)refinement
HKL-3000data reduction
HKL-3000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3CWW

3cww


Resolution: 2.908→49.699 Å / SU ML: 0.4 / σ(F): 1.34 / Phase error: 22.58 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2129 2042 2.6 %
Rwork0.1592 --
obs0.1606 78605 99.77 %
all-78800 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.908→49.699 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15558 0 200 93 15851
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00616139
X-RAY DIFFRACTIONf_angle_d0.89621801
X-RAY DIFFRACTIONf_dihedral_angle_d13.7586107
X-RAY DIFFRACTIONf_chiral_restr0.0362329
X-RAY DIFFRACTIONf_plane_restr0.0042808
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9079-2.97560.37441360.27534991X-RAY DIFFRACTION99
2.9756-3.050.29941320.2535100X-RAY DIFFRACTION100
3.05-3.13240.29471340.23145113X-RAY DIFFRACTION100
3.1324-3.22460.32561340.21085074X-RAY DIFFRACTION100
3.2246-3.32860.27921390.1925069X-RAY DIFFRACTION100
3.3286-3.44760.21411370.18595062X-RAY DIFFRACTION100
3.4476-3.58560.2241340.16585091X-RAY DIFFRACTION100
3.5856-3.74870.21931370.15985122X-RAY DIFFRACTION100
3.7487-3.94630.21811340.15185095X-RAY DIFFRACTION100
3.9463-4.19340.19091380.13725093X-RAY DIFFRACTION100
4.1934-4.5170.15771370.12265122X-RAY DIFFRACTION100
4.517-4.97120.15731360.11965132X-RAY DIFFRACTION100
4.9712-5.68960.18511300.13495117X-RAY DIFFRACTION100
5.6896-7.16490.19561390.16045140X-RAY DIFFRACTION100
7.1649-49.7060.18781450.13575242X-RAY DIFFRACTION99

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