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- PDB-4pf7: Crystal structure of insulin degrading enzyme complexed with inhibitor -

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Basic information

Entry
Database: PDB / ID: 4pf7
TitleCrystal structure of insulin degrading enzyme complexed with inhibitor
ComponentsInsulin-degrading enzyme
KeywordsHYDROLASE/HYDROLASE INHIBITOR / 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 / insulin binding / regulation of aerobic respiration / peptide catabolic process ...insulysin / ubiquitin recycling / insulin catabolic process / insulin metabolic process / amyloid-beta clearance by cellular catabolic process / hormone catabolic process / bradykinin catabolic process / 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 / positive regulation of protein binding / peroxisome / 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 / extracellular exosome / zinc ion binding / ATP binding / identical protein binding / nucleus / cytosol / cytoplasm
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 inactive domain ...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-2QW / Insulin-degrading enzyme
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.33 Å
AuthorsWang, Y. / Guo, S.
CitationJournal: J.Biol.Chem. / Year: 2015
Title: Dual Exosite-binding Inhibitors of Insulin-degrading Enzyme Challenge Its Role as the Primary Mediator of Insulin Clearance in Vivo.
Authors: Durham, T.B. / Toth, J.L. / Klimkowski, V.J. / Cao, J.X. / Siesky, A.M. / Alexander-Chacko, J. / Wu, G.Y. / Dixon, J.T. / McGee, J.E. / Wang, Y. / Guo, S.Y. / Cavitt, R.N. / Schindler, J. / ...Authors: Durham, T.B. / Toth, J.L. / Klimkowski, V.J. / Cao, J.X. / Siesky, A.M. / Alexander-Chacko, J. / Wu, G.Y. / Dixon, J.T. / McGee, J.E. / Wang, Y. / Guo, S.Y. / Cavitt, R.N. / Schindler, J. / Thibodeaux, S.J. / Calvert, N.A. / Coghlan, M.J. / Sindelar, D.K. / Christe, M. / Kiselyov, V.V. / Michael, M.D. / Sloop, K.W.
History
DepositionApr 28, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 17, 2015Provider: repository / Type: Initial release
Revision 1.1Jul 8, 2015Group: Database references
Revision 1.2Aug 26, 2015Group: Database references
Revision 1.3Sep 27, 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 / citation / database_2 / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)229,9676
Polymers228,9872
Non-polymers9804
Water10,413578
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)78.839, 115.961, 124.282
Angle α, β, γ (deg.)90.00, 97.83, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Insulin-degrading enzyme / Abeta-degrading protease / Insulin protease / Insulinase / Insulysin


Mass: 114493.484 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-2QW / (2S)-2-amino-N-{(1S)-1-cyclohexyl-2-[(4-methylphenyl)amino]-2-oxoethyl}-4-(methylselanyl)butanamide


Mass: 424.439 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H31N3O2Se
#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


Mass: 18.015 Da / Num. of mol.: 578 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.46 Å3/Da / Density % sol: 49.96 %
Crystal growTemperature: 298 K / Method: vapor diffusion / Details: 20% PEG3350, 0.2 mM sodium thiocyanate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97931 Å
DetectorType: RAYONIX MX-225 / Detector: CCD / Date: Feb 9, 2012
RadiationMonochromator: diamond(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97931 Å / Relative weight: 1
ReflectionResolution: 2.33→50 Å / Num. obs: 98275 / % possible obs: 99.4 % / Redundancy: 3.6 % / Biso Wilson estimate: 48.42 Å2 / Rsym value: 0.141 / Net I/σ(I): 5.5
Reflection shellResolution: 2.33→2.39 Å / Rmerge(I) obs: 0.65 / Mean I/σ(I) obs: 2.2 / % possible all: 98.7

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Processing

SoftwareName: BUSTER / Version: 2.11.2 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2G47

2g47


Resolution: 2.33→19.94 Å / Cor.coef. Fo:Fc: 0.9284 / Cor.coef. Fo:Fc free: 0.8951 / SU R Cruickshank DPI: 0.347 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.331 / SU Rfree Blow DPI: 0.222 / SU Rfree Cruickshank DPI: 0.228
RfactorNum. reflection% reflectionSelection details
Rfree0.2356 1050 1.12 %RANDOM
Rwork0.1989 ---
obs0.1993 94146 99.71 %-
Displacement parametersBiso mean: 45.78 Å2
Baniso -1Baniso -2Baniso -3
1--7.3016 Å20 Å2-3.171 Å2
2--2.4212 Å20 Å2
3---4.8804 Å2
Refinement stepCycle: 1 / Resolution: 2.33→19.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15660 0 54 578 16292
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00916107HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0721791HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d5706SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes444HARMONIC2
X-RAY DIFFRACTIONt_gen_planes2289HARMONIC5
X-RAY DIFFRACTIONt_it16107HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.89
X-RAY DIFFRACTIONt_other_torsion17.88
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion2027SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact18249SEMIHARMONIC4
LS refinement shellResolution: 2.33→2.39 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2224 75 1.08 %
Rwork0.2148 6864 -
all0.2148 6939 -
obs--99.71 %

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