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- PDB-2g47: Crystal structure of human insulin-degrading enzyme in complex wi... -

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Basic information

Entry
Database: PDB / ID: 2g47
TitleCrystal structure of human insulin-degrading enzyme in complex with amyloid-beta (1-40)
Components
  • Insulin-degrading enzyme
  • amyloid protein beta A4
KeywordsHYDROLASE / protein-peptide 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 / amyloid-beta complex ...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 / amyloid-beta complex / growth cone lamellipodium / cellular response to norepinephrine stimulus / growth cone filopodium / microglia development / collateral sprouting in absence of injury / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / regulation of Wnt signaling pathway / regulation of synapse structure or activity / axon midline choice point recognition / astrocyte activation involved in immune response / NMDA selective glutamate receptor signaling pathway / regulation of spontaneous synaptic transmission / mating behavior / growth factor receptor binding / insulin binding / peptidase activator activity / regulation of aerobic respiration / Golgi-associated vesicle / PTB domain binding / positive regulation of amyloid fibril formation / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / Lysosome Vesicle Biogenesis / astrocyte projection / neuron remodeling / peptide catabolic process / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / nuclear envelope lumen / dendrite development / amyloid-beta clearance / positive regulation of protein metabolic process / TRAF6 mediated NF-kB activation / peroxisomal matrix / Advanced glycosylation endproduct receptor signaling / signaling receptor activator activity / negative regulation of long-term synaptic potentiation / modulation of excitatory postsynaptic potential / The NLRP3 inflammasome / transition metal ion binding / main axon / intracellular copper ion homeostasis / regulation of multicellular organism growth / amyloid-beta metabolic process / ECM proteoglycans / regulation of presynapse assembly / positive regulation of protein binding / positive regulation of T cell migration / neuronal dense core vesicle / Purinergic signaling in leishmaniasis infection / positive regulation of chemokine production / Insulin receptor recycling / cellular response to manganese ion / Notch signaling pathway / clathrin-coated pit / negative regulation of proteolysis / extracellular matrix organization / neuron projection maintenance / Mitochondrial protein degradation / astrocyte activation / peptide binding / ionotropic glutamate receptor signaling pathway / positive regulation of calcium-mediated signaling / positive regulation of mitotic cell cycle / axonogenesis / response to interleukin-1 / protein serine/threonine kinase binding / proteolysis involved in protein catabolic process / cellular response to copper ion / platelet alpha granule lumen / cellular response to cAMP / positive regulation of glycolytic process / central nervous system development / endosome lumen / positive regulation of interleukin-1 beta production / dendritic shaft / trans-Golgi network membrane / positive regulation of long-term synaptic potentiation / adult locomotory behavior / learning / positive regulation of JNK cascade / Post-translational protein phosphorylation / Peroxisomal protein import / locomotory behavior / protein catabolic process / serine-type endopeptidase inhibitor activity / microglial cell activation / positive regulation of non-canonical NF-kappaB signal transduction / TAK1-dependent IKK and NF-kappa-B activation / regulation of long-term neuronal synaptic plasticity / cellular response to nerve growth factor stimulus
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 / Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, copper-binding domain conserved site / Amyloidogenic glycoprotein, copper-binding domain superfamily ...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 / Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, copper-binding domain conserved site / Amyloidogenic glycoprotein, copper-binding domain superfamily / Copper-binding of amyloid precursor, CuBD / Amyloid precursor protein (APP) copper-binding (CuBD) domain signature. / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide / Beta-amyloid precursor protein C-terminal / Amyloidogenic glycoprotein, intracellular domain, conserved site / Beta-amyloid precursor protein C-terminus / Amyloid precursor protein (APP) intracellular domain signature. / Amyloidogenic glycoprotein, extracellular / Amyloidogenic glycoprotein, heparin-binding / Amyloidogenic glycoprotein, E2 domain / E2 domain superfamily / Amyloidogenic glycoprotein, heparin-binding domain superfamily / Amyloid A4 N-terminal heparin-binding / E2 domain of amyloid precursor protein / Amyloid precursor protein (APP) E1 domain profile. / Amyloid precursor protein (APP) E2 domain profile. / amyloid A4 / Amyloidogenic glycoprotein / 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 / Proteinase inhibitor I2, Kunitz, conserved site / Pancreatic trypsin inhibitor (Kunitz) family signature. / BPTI/Kunitz family of serine protease inhibitors. / Pancreatic trypsin inhibitor Kunitz domain / Kunitz/Bovine pancreatic trypsin inhibitor domain / Pancreatic trypsin inhibitor (Kunitz) family profile. / Pancreatic trypsin inhibitor Kunitz domain superfamily / PH-like domain superfamily / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
1,4-DIETHYLENE DIOXIDE / Amyloid-beta precursor protein / Insulin-degrading enzyme
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsShen, Y. / Tang, W.-J.
CitationJournal: Nature / Year: 2006
Title: Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism.
Authors: Shen, Y. / Joachimiak, A. / Rosner, M.R. / Tang, W.J.
History
DepositionFeb 21, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 24, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 20, 2021Group: Database references / Derived calculations / Category: database_2 / 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 / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Feb 14, 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: amyloid protein beta A4
D: amyloid protein beta A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)238,2786
Polymers238,1024
Non-polymers1762
Water19,2041066
1
A: Insulin-degrading enzyme
C: amyloid protein beta A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)119,1393
Polymers119,0512
Non-polymers881
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2180 Å2
ΔGint-7 kcal/mol
Surface area38050 Å2
MethodPISA
2
B: Insulin-degrading enzyme
D: amyloid protein beta A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)119,1393
Polymers119,0512
Non-polymers881
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2210 Å2
ΔGint-5 kcal/mol
Surface area38190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)262.433, 262.433, 90.706
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number170
Space group name H-MP65
DetailsThe biological assembly is a monomer.

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Components

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


Mass: 114715.141 Da / Num. of mol.: 2 / Mutation: E111Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IDE / Plasmid: pProEx / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta(DE3) / References: UniProt: P14735, insulysin
#2: Protein/peptide amyloid protein beta A4


Mass: 4335.852 Da / Num. of mol.: 2 / Source method: obtained synthetically
Details: This sequence occurs naturally in Homo sapiens (Humans)
References: UniProt: P05067*PLUS
#3: Chemical ChemComp-DIO / 1,4-DIETHYLENE DIOXIDE


Mass: 88.105 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H8O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1066 / 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: 3.78 Å3/Da / Density % sol: 67.49 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 10% PEGMME 5000, 0.1M HEPES, 10% diaoxane, 5% tacsimate, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.9 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Aug 23, 2005
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9 Å / Relative weight: 1
ReflectionResolution: 2.1→30 Å / Num. all: 194459 / Num. obs: 194459 / % possible obs: 99 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 7.6 % / Biso Wilson estimate: 19.2 Å2 / Rsym value: 0.076 / Net I/σ(I): 24.2
Reflection shellResolution: 2.1→2.18 Å / Redundancy: 4.4 % / Rmerge(I) obs: 0.55 / Mean I/σ(I) obs: 2.3 / % possible all: 77

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Processing

Software
NameVersionClassification
CNS1.1refinement
HKL-2000data reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→29.77 Å / Rfactor Rfree error: 0.002 / Data cutoff high absF: 114223.13 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.223 18633 10 %RANDOM
Rwork0.203 ---
obs0.203 187264 90.5 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 52.4308 Å2 / ksol: 0.37074 e/Å3
Displacement parametersBiso mean: 34.6 Å2
Baniso -1Baniso -2Baniso -3
1--3.06 Å21.21 Å20 Å2
2---3.06 Å20 Å2
3---6.12 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.27 Å0.24 Å
Luzzati d res low-5 Å
Luzzati sigma a0.25 Å0.22 Å
Refinement stepCycle: LAST / Resolution: 2.1→29.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15884 0 12 1066 16962
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.3
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d23.1
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.81
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.291.5
X-RAY DIFFRACTIONc_mcangle_it1.92
X-RAY DIFFRACTIONc_scbond_it2.312
X-RAY DIFFRACTIONc_scangle_it3.462.5
LS refinement shellResolution: 2.1→2.23 Å / Rfactor Rfree error: 0.006 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.277 2333 9.9 %
Rwork0.26 21339 -
obs--69 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2water_rep.paramwater.top
X-RAY DIFFRACTION3dox.pardox.top

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