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- PDB-2g48: crystal structure of human insulin-degrading enzyme in complex wi... -

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Basic information

Entry
Database: PDB / ID: 2g48
Titlecrystal structure of human insulin-degrading enzyme in complex with amylin
Components
  • Insulin-degrading enzyme
  • Islet amyloid polypeptideAmylin
KeywordsHYDROLASE / protein-peptide complex
Function / homology
Function and homology information


insulysin / : / ubiquitin recycling / insulin catabolic process / insulin metabolic process / amylin receptor signaling pathway / Calcitonin-like ligand receptors / amyloid-beta clearance by cellular catabolic process / hormone catabolic process / bradykinin catabolic process ...insulysin / : / ubiquitin recycling / insulin catabolic process / insulin metabolic process / amylin receptor signaling pathway / Calcitonin-like ligand receptors / amyloid-beta clearance by cellular catabolic process / hormone catabolic process / bradykinin catabolic process / negative regulation of amyloid fibril formation / negative regulation of bone resorption / ubiquitin-dependent protein binding / insulin binding / eating behavior / regulation of aerobic respiration / peptide catabolic process / amyloid-beta clearance / negative regulation of osteoclast differentiation / positive regulation of protein kinase A signaling / Regulation of gene expression in beta cells / peroxisomal matrix / negative regulation of protein-containing complex assembly / positive regulation of cAMP-mediated signaling / positive regulation of calcium-mediated signaling / amyloid-beta metabolic process / bone resorption / sensory perception of pain / Insulin receptor recycling / proteolysis involved in protein catabolic process / osteoclast differentiation / Peroxisomal protein import / peptide binding / protein catabolic process / hormone activity / metalloendopeptidase activity / antigen processing and presentation of endogenous peptide antigen via MHC class I / peroxisome / positive regulation of protein catabolic process / cell-cell signaling / virus receptor activity / insulin receptor signaling pathway / amyloid-beta binding / positive regulation of protein binding / G alpha (s) signalling events / basolateral plasma membrane / endopeptidase activity / positive regulation of MAPK cascade / receptor ligand activity / Ub-specific processing proteases / positive regulation of apoptotic process / Amyloid fiber formation / external side of plasma membrane / signaling receptor binding / lipid binding / apoptotic process / cell surface / signal transduction / protein homodimerization activity / mitochondrion / proteolysis / extracellular space / extracellular exosome / zinc ion binding / extracellular region / ATP binding / nucleus / identical protein binding / cytosol / cytoplasm
Similarity search - Function
Peptidase M16, middle/third domain / Middle or third domain of peptidase_M16 / Islet amyloid polypeptide / Calcitonin-like / Calcitonin peptide-like / Calcitonin, conserved site / Calcitonin / CGRP / IAPP family signature. / calcitonin / Calcitonin/adrenomedullin / Calcitonin / CGRP / IAPP family ...Peptidase M16, middle/third domain / Middle or third domain of peptidase_M16 / Islet amyloid polypeptide / Calcitonin-like / Calcitonin peptide-like / Calcitonin, conserved site / Calcitonin / CGRP / IAPP family signature. / calcitonin / Calcitonin/adrenomedullin / Calcitonin / CGRP / IAPP family / 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
1,4-DIETHYLENE DIOXIDE / Islet amyloid polypeptide / Insulin-degrading enzyme / Insulin-degrading enzyme
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 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: Islet amyloid polypeptide
D: Islet amyloid polypeptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)237,4256
Polymers237,2494
Non-polymers1762
Water12,538696
1
A: Insulin-degrading enzyme
C: Islet amyloid polypeptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)118,7133
Polymers118,6242
Non-polymers881
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2320 Å2
ΔGint-3 kcal/mol
Surface area38940 Å2
MethodPISA
2
B: Insulin-degrading enzyme
D: Islet amyloid polypeptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)118,7133
Polymers118,6242
Non-polymers881
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2580 Å2
ΔGint-6 kcal/mol
Surface area38460 Å2
MethodPISA
Unit cell
Length a, b, c (Å)262.281, 262.281, 91.106
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: Q5T5N2, UniProt: P14735*PLUS, insulysin
#2: Protein/peptide Islet amyloid polypeptide / Amylin / Diabetes-associated peptide / DAP / Amylin / Insulinoma amyloid peptide


Mass: 3909.304 Da / Num. of mol.: 2 / Fragment: residues 34-70 / Source method: obtained synthetically
Details: This sequence occurs naturally in Homo sapiens (Humans)
References: UniProt: P10997
#3: Chemical ChemComp-DIO / 1,4-DIETHYLENE DIOXIDE / 1,4-Dioxane


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


Mass: 18.015 Da / Num. of mol.: 696 / 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: 3.81 Å3/Da / Density % sol: 67.71 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7
Details: PEGMME5000, Dioxane, Tacsimate, HEPES , 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: 2.6→30 Å / Num. all: 108791 / Num. obs: 108791 / % possible obs: 99 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 5.6 % / Biso Wilson estimate: 30.3 Å2 / Rsym value: 0.104 / Net I/σ(I): 18.9
Reflection shellResolution: 2.6→2.69 Å / Redundancy: 5.2 % / Mean I/σ(I) obs: 5.2 / Rsym value: 0.036 / % possible all: 98.9

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Processing

Software
NameVersionClassification
CNS1.1refinement
HKL-2000data reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→29.77 Å / Rfactor Rfree error: 0.002 / Data cutoff high absF: 105599.12 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.225 10587 10 %RANDOM
Rwork0.196 ---
obs0.196 105819 96.4 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 39.0439 Å2 / ksol: 0.377792 e/Å3
Displacement parametersBiso mean: 30.7 Å2
Baniso -1Baniso -2Baniso -3
1--3.12 Å24.03 Å20 Å2
2---3.12 Å20 Å2
3---6.23 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.31 Å0.26 Å
Luzzati d res low-5 Å
Luzzati sigma a0.3 Å0.22 Å
Refinement stepCycle: LAST / Resolution: 2.6→29.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms16001 0 12 696 16709
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
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_d23.3
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.89
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.161.5
X-RAY DIFFRACTIONc_mcangle_it1.892
X-RAY DIFFRACTIONc_scbond_it2.092
X-RAY DIFFRACTIONc_scangle_it3.172.5
LS refinement shellResolution: 2.6→2.76 Å / Rfactor Rfree error: 0.007 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.264 1631 10 %
Rwork0.22 14745 -
obs--89.9 %
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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