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- PDB-4m1c: Crystal Structure Analysis of Fab-Bound Human Insulin Degrading E... -

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Basic information

Entry
Database: PDB / ID: 4m1c
TitleCrystal Structure Analysis of Fab-Bound Human Insulin Degrading Enzyme (IDE) in Complex with Amyloid-Beta (1-40)
Components
  • Amyloid beta A4 protein
  • Fab-bound IDE, heavy chain
  • Fab-bound IDE, light chain
  • Insulin-degrading enzyme
KeywordsHYDROLASE / Zinc metalloprotease
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 / cytosolic mRNA polyadenylation ...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 / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / Formyl peptide receptors bind formyl peptides and many other ligands / 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 / regulation of Wnt signaling pathway / mating behavior / positive regulation of amyloid fibril formation / ubiquitin-modified protein reader activity / ciliary rootlet / Lysosome Vesicle Biogenesis / insulin binding / PTB domain binding / Golgi-associated vesicle / neuron remodeling / regulation of aerobic respiration / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / : / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / presynaptic active zone / nuclear envelope lumen / peptide catabolic process / modulation of excitatory postsynaptic potential / suckling behavior / COPII-coated ER to Golgi transport vesicle / dendrite development / amyloid-beta clearance / smooth endoplasmic reticulum / regulation of NMDA receptor activity / TRAF6 mediated NF-kB activation / negative regulation of long-term synaptic potentiation / peroxisomal matrix / Advanced glycosylation endproduct receptor signaling / neuromuscular process controlling balance / regulation of presynapse assembly / The NLRP3 inflammasome / intracellular copper ion homeostasis / transition metal ion binding / regulation of multicellular organism growth / negative regulation of neuron differentiation / ECM proteoglycans / spindle midzone / positive regulation of T cell migration / Purinergic signaling in leishmaniasis infection / positive regulation of calcium-mediated signaling / amyloid-beta metabolic process / forebrain development / regulation of peptidyl-tyrosine phosphorylation / positive regulation of chemokine production / clathrin-coated pit / Notch signaling pathway / cholesterol metabolic process / Insulin receptor recycling / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of protein metabolic process / ionotropic glutamate receptor signaling pathway / neuron projection maintenance / positive regulation of glycolytic process / extracellular matrix organization / proteolysis involved in protein catabolic process / positive regulation of mitotic cell cycle / response to interleukin-1 / axonogenesis / adult locomotory behavior / trans-Golgi network membrane / dendritic shaft / locomotory behavior / platelet alpha granule lumen / 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 / astrocyte activation / endosome lumen / Post-translational protein phosphorylation / Peroxisomal protein import / synapse organization / peptide binding / microglial cell activation / regulation of long-term neuronal synaptic plasticity / positive regulation of JNK cascade / protein catabolic process / TAK1-dependent IKK and NF-kappa-B activation / neuromuscular junction
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 / Peptidase M16, zinc-binding site / Insulinase family, zinc-binding region signature. / 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. / 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 / Immunoglobulins / Immunoglobulin-like / Sandwich / 2-Layer Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Amyloid-beta precursor protein / Insulin-degrading enzyme
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.5007 Å
AuthorsMcCord, L.M. / Liang, W. / Farcasanu, M. / Scherpelz, K. / Meredith, S.C. / Koide, S. / Tang, W.J.
CitationJournal: To be Published
Title: Crystal Structure Analysis of Fab-Bound Human Insulin Degrading Enzyme (IDE) in Complex with Amyloid-Beta (1-40)
Authors: McCord, L.A. / Liang, W. / Farcasanu, M. / Scherpelz, K. / Meredith, S.C. / Koide, S. / Tang, W.J.
History
DepositionAug 2, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 6, 2014Provider: repository / Type: Initial release
Revision 1.1Oct 1, 2014Group: Source and taxonomy
Revision 1.2Oct 8, 2014Group: Derived calculations
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_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_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_conn.ptnr2_label_seq_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
C: Fab-bound IDE, heavy chain
D: Fab-bound IDE, light chain
E: Fab-bound IDE, heavy chain
F: Fab-bound IDE, light chain
G: Amyloid beta A4 protein
H: Amyloid beta A4 protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)346,29110
Polymers346,1608
Non-polymers1312
Water0
1
A: Insulin-degrading enzyme
C: Fab-bound IDE, heavy chain
D: Fab-bound IDE, light chain
G: Amyloid beta A4 protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)173,1465
Polymers173,0804
Non-polymers651
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Insulin-degrading enzyme
E: Fab-bound IDE, heavy chain
F: Fab-bound IDE, light chain
H: Amyloid beta A4 protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)173,1465
Polymers173,0804
Non-polymers651
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)56.583, 135.324, 368.524
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
22
33
44
/ NCS ensembles :
ID
1
2
3
4

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Components

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


Mass: 114560.578 Da / Num. of mol.: 2 / Mutation: E111Q
Source method: isolated from a genetically manipulated source
Details: Cysteine-Free / Source: (gene. exp.) Homo sapiens (human) / Gene: IDE, Insulin Degrading Enzyme / Production host: Escherichia coli (E. coli) / References: UniProt: P14735, insulysin
#2: Antibody Fab-bound IDE, heavy chain


Mass: 28201.670 Da / Num. of mol.: 2 / Source method: obtained synthetically
Details: Specific antigen-binding fragment (Fab, light chain) synthetically engineered to target Human Insulin Degrading Enzyme
Source: (synth.) Homo sapiens (human)
#3: Antibody Fab-bound IDE, light chain


Mass: 25982.098 Da / Num. of mol.: 2 / Source method: obtained synthetically
Details: Specific antigen-binding fragment (Fab, heavy chain) synthetically engineered to target Human Insulin Degrading Enzyme
Source: (synth.) Homo sapiens (human)
#4: Protein/peptide Amyloid beta A4 protein / ABPP / APPI / APP / Alzheimer disease amyloid protein / Cerebral vascular amyloid peptide / CVAP / ...ABPP / APPI / APP / Alzheimer disease amyloid protein / Cerebral vascular amyloid peptide / CVAP / PreA4 / Protease nexin-II / PN-II / N-APP / Soluble APP-alpha / S-APP-alpha / Soluble APP-beta / S-APP-beta / C99 / Beta-amyloid protein 42 / Beta-APP42 / Beta-amyloid protein 40 / Beta-APP40 / C83 / P3(42) / P3(40) / C80 / Gamma-secretase C-terminal fragment 59 / Amyloid intracellular domain 59 / AICD-59 / AID(59) / Gamma-CTF(59) / Gamma-secretase C-terminal fragment 57 / Amyloid intracellular domain 57 / AICD-57 / AID(57) / Gamma-CTF(57) / Gamma-secretase C-terminal fragment 50 / Amyloid intracellular domain 50 / AICD-50 / AID(50) / Gamma-CTF(50) / C31


Mass: 4335.852 Da / Num. of mol.: 2 / Source method: obtained synthetically / Details: Amyloid-Beta (1-40) / Source: (synth.) Homo sapiens (human) / References: UniProt: P05067
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn

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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: 2.04 Å3/Da / Density % sol: 39.65 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.1M Sodium cacodylate, pH6.5, 0.2M MgCl2, 10% PEG-3000, VAPOR DIFFUSION, HANGING DROP, temperature 291.15K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.9792 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 10, 2013
RadiationMonochromator: MAR CCD / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 3.5→49.1 Å / Num. all: 35563 / Num. obs: 35563 / % possible obs: 96.6 % / Redundancy: 5.5 % / Biso Wilson estimate: 52.45 Å2 / Rmerge(I) obs: 0.159
Reflection shellResolution: 3.5→3.56 Å / Redundancy: 5.6 % / Rmerge(I) obs: 0.68 / % possible all: 96.7

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Processing

Software
NameVersionClassification
HKL-3000data collection
PHASESphasing
PHENIX(phenix.refine: 1.8.2_1309)refinement
HKL-3000data reduction
HKL-3000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4IOF

4iof


Resolution: 3.5007→49.064 Å / SU ML: 0.45 / σ(F): 1.34 / Phase error: 26.98 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.27 1997 5.62 %
Rwork0.2278 --
obs0.2302 35509 96.25 %
all-34536 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.5007→49.064 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms21507 0 2 0 21509
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00222028
X-RAY DIFFRACTIONf_angle_d0.53329811
X-RAY DIFFRACTIONf_dihedral_angle_d9.7458120
X-RAY DIFFRACTIONf_chiral_restr0.0213259
X-RAY DIFFRACTIONf_plane_restr0.0033816
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.5007-3.58820.32761370.29342289X-RAY DIFFRACTION94
3.5882-3.68520.3241430.2812409X-RAY DIFFRACTION99
3.6852-3.79360.34881380.27592319X-RAY DIFFRACTION95
3.7936-3.9160.35551420.27422401X-RAY DIFFRACTION99
3.916-4.05590.31831410.25652354X-RAY DIFFRACTION94
4.0559-4.21820.29851420.25142393X-RAY DIFFRACTION99
4.2182-4.41010.27861420.22262366X-RAY DIFFRACTION95
4.4101-4.64240.251410.2122380X-RAY DIFFRACTION97
4.6424-4.9330.23631420.20112383X-RAY DIFFRACTION97
4.933-5.31350.27331420.20872365X-RAY DIFFRACTION95
5.3135-5.84740.26471430.22872403X-RAY DIFFRACTION95
5.8474-6.69170.28151440.24032394X-RAY DIFFRACTION96
6.6917-8.42390.2271440.222422X-RAY DIFFRACTION95
8.4239-49.06890.21941560.18572634X-RAY DIFFRACTION97
Refinement TLS params.Method: refined / Origin x: 13.9556 Å / Origin y: -8.5682 Å / Origin z: -98.8944 Å
111213212223313233
T0.3352 Å2-0.0212 Å2-0.0597 Å2-0.4054 Å20.0085 Å2--0.4926 Å2
L0.3628 °20.0472 °2-0.2509 °2-0.1707 °2-0.0427 °2--0.7052 °2
S0.0539 Å °-0.1229 Å °-0.0226 Å °0.0264 Å °-0.0403 Å °0.0183 Å °-0.0591 Å °0.0657 Å °-0.0129 Å °
Refinement TLS groupSelection details: all

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