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- PDB-2wk3: Crystal structure of human insulin-degrading enzyme in complex wi... -

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Basic information

Entry
Database: PDB / ID: 2wk3
TitleCrystal structure of human insulin-degrading enzyme in complex with amyloid-beta (1-42)
Components
  • BETA-AMYLOID PROTEIN 42Amyloid beta
  • INSULIN DEGRADING ENZYMEInsulin-degrading enzyme
KeywordsHYDROLASE / METAL-BINDING / METALLOPROTEASE / IDE / PROTEASE / AMYLOID-BETA (1-42)
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 / regulation of epidermal growth factor-activated receptor activity / signaling receptor activator activity / collateral sprouting in absence of injury ...insulysin / ubiquitin recycling / insulin catabolic process / insulin metabolic process / amyloid-beta clearance by cellular catabolic process / hormone catabolic process / bradykinin catabolic process / regulation of epidermal growth factor-activated receptor activity / signaling receptor activator activity / collateral sprouting in absence of injury / cytosolic mRNA polyadenylation / microglia development / regulation of synapse structure or activity / Formyl peptide receptors bind formyl peptides and many other ligands / regulation of Wnt signaling pathway / axo-dendritic transport / synaptic assembly at neuromuscular junction / smooth endoplasmic reticulum calcium ion homeostasis / axon midline choice point recognition / astrocyte activation involved in immune response / regulation of spontaneous synaptic transmission / mating behavior / NMDA selective glutamate receptor signaling pathway / ubiquitin-modified protein reader activity / ciliary rootlet / Lysosome Vesicle Biogenesis / insulin binding / PTB domain binding / Golgi-associated vesicle / regulation of aerobic respiration / positive regulation of amyloid fibril formation / neuron remodeling / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / protein serine/threonine kinase binding / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / : / peptide catabolic process / nuclear envelope lumen / suckling behavior / amyloid-beta clearance / presynaptic active zone / dendrite development / COPII-coated ER to Golgi transport vesicle / modulation of excitatory postsynaptic potential / peroxisomal matrix / TRAF6 mediated NF-kB activation / Advanced glycosylation endproduct receptor signaling / neuromuscular process controlling balance / The NLRP3 inflammasome / regulation of presynapse assembly / transition metal ion binding / regulation of multicellular organism growth / intracellular copper ion homeostasis / negative regulation of long-term synaptic potentiation / negative regulation of neuron differentiation / ECM proteoglycans / smooth endoplasmic reticulum / Mitochondrial protein degradation / positive regulation of T cell migration / spindle midzone / amyloid-beta metabolic process / Purinergic signaling in leishmaniasis infection / positive regulation of calcium-mediated signaling / forebrain development / clathrin-coated pit / regulation of peptidyl-tyrosine phosphorylation / positive regulation of chemokine production / Notch signaling pathway / Insulin receptor recycling / positive regulation of G2/M transition of mitotic cell cycle / neuron projection maintenance / positive regulation of protein metabolic process / ionotropic glutamate receptor signaling pathway / positive regulation of glycolytic process / cholesterol metabolic process / response to interleukin-1 / positive regulation of mitotic cell cycle / extracellular matrix organization / axonogenesis / adult locomotory behavior / proteolysis involved in protein catabolic process / trans-Golgi network membrane / dendritic shaft / platelet alpha granule lumen / locomotory behavior / positive regulation of peptidyl-threonine phosphorylation / learning / positive regulation of interleukin-1 beta production / central nervous system development / positive regulation of long-term synaptic potentiation / endosome lumen / astrocyte activation / Peroxisomal protein import / peptide binding / Post-translational protein phosphorylation / positive regulation of JNK cascade / synapse organization / regulation of long-term neuronal synaptic plasticity / microglial cell activation / TAK1-dependent IKK and NF-kappa-B activation
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 / 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 ...Peptidase M16, middle/third domain / Middle or third domain of peptidase_M16 / 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 / Peptidase M16, zinc-binding site / Insulinase family, zinc-binding region signature. / 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. / Amyloid precursor protein (APP) E1 domain profile. / Amyloid precursor protein (APP) E2 domain profile. / 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 A4 / Amyloidogenic glycoprotein / 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
Amyloid-beta precursor protein / Insulin-degrading enzyme
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 2.59 Å
AuthorsGuo, Q. / Tang, W.J.
CitationJournal: J.Mol.Biol. / Year: 2010
Title: Molecular Basis for the Recognition and Cleavages of Igf-II, Tgf-Alpha, and Amylin by Human Insulin Degrading Enzyme.
Authors: Guo, Q. / Manolopoulou, M. / Bian, Y. / Schilling, A.B. / Tang, W.J.
History
DepositionJun 5, 2009Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 3, 2009Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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.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_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_conn.ptnr2_label_seq_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Remark 700 SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN ... SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN THE SHEET RECORDS BELOW, TWO SHEETS ARE DEFINED.

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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: BETA-AMYLOID PROTEIN 42
D: BETA-AMYLOID PROTEIN 42
hetero molecules


Theoretical massNumber of molelcules
Total (without water)245,1086
Polymers244,9784
Non-polymers1312
Water4,216234
1
B: INSULIN DEGRADING ENZYME
D: BETA-AMYLOID PROTEIN 42
hetero molecules


Theoretical massNumber of molelcules
Total (without water)122,5543
Polymers122,4892
Non-polymers651
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2040 Å2
ΔGint-48.85 kcal/mol
Surface area37960 Å2
MethodPISA
2
A: INSULIN DEGRADING ENZYME
C: BETA-AMYLOID PROTEIN 42
hetero molecules


Theoretical massNumber of molelcules
Total (without water)122,5543
Polymers122,4892
Non-polymers651
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2000 Å2
ΔGint-49.27 kcal/mol
Surface area38080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)261.628, 261.628, 90.675
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 / Insulin-degrading enzyme / INSULIN PROTEASE / INSULYSIN / INSULINASE


Mass: 117968.664 Da / Num. of mol.: 2 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P14735, insulysin
#2: Protein/peptide BETA-AMYLOID PROTEIN 42 / Amyloid beta / BETA-APP42 / AMYLOID BETA A4 PROTEIN SYNONYM: AMYLOID BETA / ALZHEIMER DISEASE AMYLOID PROTEIN / ...BETA-APP42 / AMYLOID BETA A4 PROTEIN SYNONYM: AMYLOID BETA / ALZHEIMER DISEASE AMYLOID PROTEIN / ABPP / APPI / APP / PREA4 / CEREBRAL VASCULAR AMYLOID PEPTIDE / CVAP / PROTEASE NEXIN-II / PN-II SYNONYM: APP / ABPP / ALZHEIMER'S DISEASE AMYLOID PROTEIN / CEREBRAL VASCULAR AMYLOID PEPTIDE / CVAP / PROTEASE NEXIN-II / PN-II / APPI


Mass: 4520.087 Da / Num. of mol.: 2 / Fragment: BETA-AMYLOID PROTEIN 42, RESIDUES 672-713
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI BL21(DE3) (bacteria) / References: UniProt: P05067
#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 / Water


Mass: 18.015 Da / Num. of mol.: 234 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE IN CHAIN A, CYS 110 TO LEU ENGINEERED RESIDUE IN CHAIN A, GLU 111 TO GLN ...ENGINEERED RESIDUE IN CHAIN A, CYS 110 TO LEU ENGINEERED RESIDUE IN CHAIN A, GLU 111 TO GLN ENGINEERED RESIDUE IN CHAIN A, CYS 171 TO SER ENGINEERED RESIDUE IN CHAIN A, CYS 178 TO ALA ENGINEERED RESIDUE IN CHAIN A, CYS 257 TO VAL ENGINEERED RESIDUE IN CHAIN A, CYS 414 TO LEU ENGINEERED RESIDUE IN CHAIN A, CYS 573 TO ASN ENGINEERED RESIDUE IN CHAIN A, CYS 590 TO SER ENGINEERED RESIDUE IN CHAIN A, CYS 789 TO SER ENGINEERED RESIDUE IN CHAIN A, CYS 812 TO ALA ENGINEERED RESIDUE IN CHAIN A, CYS 819 TO ALA ENGINEERED RESIDUE IN CHAIN A, CYS 904 TO SER ENGINEERED RESIDUE IN CHAIN A, CYS 966 TO ASN ENGINEERED RESIDUE IN CHAIN A, CYS 974 TO ALA ENGINEERED RESIDUE IN CHAIN B, CYS 110 TO LEU ENGINEERED RESIDUE IN CHAIN B, GLU 111 TO GLN ENGINEERED RESIDUE IN CHAIN B, CYS 171 TO SER ENGINEERED RESIDUE IN CHAIN B, CYS 178 TO ALA ENGINEERED RESIDUE IN CHAIN B, CYS 257 TO VAL ENGINEERED RESIDUE IN CHAIN B, CYS 414 TO LEU ENGINEERED RESIDUE IN CHAIN B, CYS 573 TO ASN ENGINEERED RESIDUE IN CHAIN B, CYS 590 TO SER ENGINEERED RESIDUE IN CHAIN B, CYS 789 TO SER ENGINEERED RESIDUE IN CHAIN B, CYS 812 TO ALA ENGINEERED RESIDUE IN CHAIN B, CYS 819 TO ALA ENGINEERED RESIDUE IN CHAIN B, CYS 904 TO SER ENGINEERED RESIDUE IN CHAIN B, CYS 966 TO ASN ENGINEERED RESIDUE IN CHAIN B, CYS 974 TO ALA

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 4.02 Å3/Da / Density % sol: 69.17 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 1.0333
DetectorType: ADSC CCD / Detector: CCD / Date: Feb 21, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0333 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. obs: 104637 / % possible obs: 99 % / Observed criterion σ(I): 1 / Redundancy: 3.6 % / Biso Wilson estimate: 16.4 Å2 / Rmerge(I) obs: 0.09 / Net I/σ(I): 17.6

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Processing

SoftwareName: REFMAC / Version: 5.5.0088 / Classification: refinement
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 2.59→49.44 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.919 / SU B: 7.958 / SU ML: 0.171 / Cross valid method: THROUGHOUT / ESU R: 0.306 / ESU R Free: 0.238 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.232 5511 5 %RANDOM
Rwork0.187 ---
obs0.189 104637 99.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 37.79 Å2
Baniso -1Baniso -2Baniso -3
1--0.02 Å2-0.01 Å20 Å2
2---0.02 Å20 Å2
3---0.02 Å2
Refinement stepCycle: LAST / Resolution: 2.59→49.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15659 0 2 234 15895
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0220.02216051
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.9591.96321739
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.77251926
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.81824.582790
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.783152801
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.5161576
X-RAY DIFFRACTIONr_chiral_restr0.1340.22356
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.02112260
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_it0.9271.59678
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.832215620
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.22536373
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it5.3294.56119
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.59→2.66 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.329 388 -
Rwork0.271 7620 -
obs--99.71 %

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