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- PDB-4nxo: Crystal Structure of Insulin Degrading Enzyme in complex with BDM44768 -

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Basic information

Entry
Database: PDB / ID: 4nxo
TitleCrystal Structure of Insulin Degrading Enzyme in complex with BDM44768
ComponentsInsulin-degrading enzyme
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Hydrolase / Inhibitor / Cysteine free / 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-2H7 / 1,4-DIETHYLENE DIOXIDE / DI(HYDROXYETHYL)ETHER / Insulin-degrading enzyme
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.73 Å
AuthorsLiang, W.G. / Deprez, R. / Deprez, B. / Tang, W.
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
DepositionDec 9, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 7, 2015Provider: repository / Type: Initial release
Revision 1.1Oct 14, 2015Group: Data collection
Revision 1.2Oct 28, 2015Group: Database references
Revision 1.3Sep 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_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_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)232,17922
Polymers229,1212
Non-polymers3,05820
Water2,720151
1
A: Insulin-degrading enzyme
hetero molecules


Theoretical massNumber of molelcules
Total (without water)115,99310
Polymers114,5611
Non-polymers1,4329
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Insulin-degrading enzyme
hetero molecules


Theoretical massNumber of molelcules
Total (without water)116,18712
Polymers114,5611
Non-polymers1,62611
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)262.909, 262.909, 86.337
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number170
Space group name H-MP65
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
21

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection details
111chain A
211chain B

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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: 114560.578 Da / Num. of mol.: 2 / Fragment: UNP residues 42-1019
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 , 8 types, 171 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-2H7 / 4-fluoro-N-({1-[(2R)-4-(hydroxyamino)-1-(naphthalen-2-yl)-4-oxobutan-2-yl]-1H-1,2,3-triazol-4-yl}methyl)benzamide


Mass: 447.462 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H22FN5O3
#4: Chemical ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400


Mass: 238.278 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H22O6 / Comment: precipitant*YM
#5: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C4H10O3
#6: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#7: 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
#8: Chemical ChemComp-DIO / 1,4-DIETHYLENE DIOXIDE


Mass: 88.105 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H8O2
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 151 / 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: 3.76 Å3/Da / Density % sol: 67.24 %
Crystal growTemperature: 291.15 K / pH: 7
Details: 0.1M HEPES, pH 7.0, 10% Tacsimate, 10%Dioxane, 10% PEG-5000, VAPOR DIFFUSION, HANGING DROP, temperature 291.15K

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Data collection

DiffractionMean temperature: 120 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 1
DetectorType: ADSC QUANTUM 315 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.73→50 Å / Num. obs: 90103 / % possible obs: 99 % / Observed criterion σ(I): 3.03 / Redundancy: 4.9 % / Rmerge(I) obs: 0.137 / Net I/σ(I): 10.81
Reflection shellResolution: 2.75→2.8 Å / Redundancy: 3.3 % / Mean I/σ(I) obs: 1.96 / % possible all: 100

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Processing

Software
NameVersionClassification
HKL-3000data collection
PHENIXmodel building
PHENIX(phenix.refine: 1.8.4_1496)refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3CWW

3cww


Resolution: 2.73→43.82 Å / SU ML: 0.35 / σ(F): 1.34 / Phase error: 27.3 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.219 1999 2.22 %
Rwork0.17 --
obs0.171 90026 99.5 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.73→43.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15564 0 198 151 15913
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00416144
X-RAY DIFFRACTIONf_angle_d0.76121810
X-RAY DIFFRACTIONf_dihedral_angle_d13.6676107
X-RAY DIFFRACTIONf_chiral_restr0.0312331
X-RAY DIFFRACTIONf_plane_restr0.0032809
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDType
11A9392X-RAY DIFFRACTIONPOSITIONAL
12B9392X-RAY DIFFRACTIONPOSITIONAL
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7329-2.80130.3571330.28545941X-RAY DIFFRACTION94
2.8013-2.8770.34031390.26756270X-RAY DIFFRACTION100
2.877-2.96160.30961430.25736252X-RAY DIFFRACTION100
2.9616-3.05720.32311410.24386282X-RAY DIFFRACTION100
3.0572-3.16650.33981460.23286268X-RAY DIFFRACTION100
3.1665-3.29320.29231400.21786289X-RAY DIFFRACTION100
3.2932-3.4430.26131430.19786284X-RAY DIFFRACTION100
3.443-3.62450.2511450.18056291X-RAY DIFFRACTION100
3.6245-3.85140.23341410.16126293X-RAY DIFFRACTION100
3.8514-4.14860.18451470.14996324X-RAY DIFFRACTION100
4.1486-4.56570.19691440.13216331X-RAY DIFFRACTION100
4.5657-5.22540.16291450.13086339X-RAY DIFFRACTION100
5.2254-6.57990.18711460.15596394X-RAY DIFFRACTION100
6.5799-43.82380.14811460.13726469X-RAY DIFFRACTION99

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