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- PDB-4nge: Crystal Structure of Human Presequence Protease in Complex with A... -

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Basic information

Entry
Database: PDB / ID: 4nge
TitleCrystal Structure of Human Presequence Protease in Complex with Amyloid-beta (1-40)
Components
  • (Beta-amyloid protein ...) x 2
  • (Presequence protease, ...) x 2
KeywordsHYDROLASE/PROTEIN BINDING / M16 metalloprotease / Alzheimer's disease / zinc metalloendoprotease / monomethyllysine / dimethyllysine / S-(dimethylarsenic)cysteine / mitochondrial matrix / HYDROLASE-PROTEIN BINDING complex
Function / homology
Function and homology information


Mitochondrial protein import / amyloid-beta complex / negative regulation of presynapse assembly / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases / regulation of Wnt signaling pathway / synaptic assembly at neuromuscular junction ...Mitochondrial protein import / amyloid-beta complex / negative regulation of presynapse assembly / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases / regulation of Wnt signaling pathway / synaptic assembly at neuromuscular junction / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / axon midline choice point recognition / smooth endoplasmic reticulum calcium ion homeostasis / astrocyte activation involved in immune response / NMDA selective glutamate receptor signaling pathway / mating behavior / regulation of spontaneous synaptic transmission / protein targeting to mitochondrion / ciliary rootlet / Golgi-associated vesicle / PTB domain binding / Lysosome Vesicle Biogenesis / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / positive regulation of amyloid fibril formation / neuron remodeling / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / nuclear envelope lumen / COPII-coated ER to Golgi transport vesicle / suckling behavior / signaling receptor activator activity / dendrite development / modulation of excitatory postsynaptic potential / TRAF6 mediated NF-kB activation / presynaptic active zone / positive regulation of protein metabolic process / neuromuscular process controlling balance / Advanced glycosylation endproduct receptor signaling / The NLRP3 inflammasome / negative regulation of long-term synaptic potentiation / regulation of presynapse assembly / regulation of multicellular organism growth / transition metal ion binding / intracellular copper ion homeostasis / negative regulation of neuron differentiation / ECM proteoglycans / spindle midzone / positive regulation of T cell migration / smooth endoplasmic reticulum / Purinergic signaling in leishmaniasis infection / forebrain development / positive regulation of chemokine production / clathrin-coated pit / Notch signaling pathway / protein serine/threonine kinase binding / positive regulation of G2/M transition of mitotic cell cycle / extracellular matrix organization / neuron projection maintenance / Mitochondrial protein degradation / response to interleukin-1 / ionotropic glutamate receptor signaling pathway / positive regulation of mitotic cell cycle / cholesterol metabolic process / axonogenesis / positive regulation of calcium-mediated signaling / enzyme activator activity / dendritic shaft / platelet alpha granule lumen / adult locomotory behavior / positive regulation of glycolytic process / central nervous system development / learning / positive regulation of interleukin-1 beta production / trans-Golgi network membrane / positive regulation of long-term synaptic potentiation / endosome lumen / locomotory behavior / astrocyte activation / Post-translational protein phosphorylation / positive regulation of JNK cascade / microglial cell activation / regulation of long-term neuronal synaptic plasticity / serine-type endopeptidase inhibitor activity / synapse organization / TAK1-dependent IKK and NF-kappa-B activation / positive regulation of non-canonical NF-kappaB signal transduction / neuromuscular junction / visual learning / protein processing / recycling endosome / metalloendopeptidase activity / positive regulation of interleukin-6 production / Golgi lumen / cognition / neuron cellular homeostasis / positive regulation of inflammatory response / endocytosis / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / cellular response to amyloid-beta / metallopeptidase activity
Similarity search - Function
: / Peptidase M16C associated / Peptidase M16C associated / PreP C-terminal domain / Peptidase M16C associated / 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 M16C associated / Peptidase M16C associated / PreP C-terminal domain / Peptidase M16C associated / 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, 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
ACETATE ION / Amyloid-beta precursor protein / Presequence protease, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / molecular replacement/SAD / Resolution: 2.704 Å
AuthorsKing, J.V. / Liang, W.G. / Tang, W.J.
CitationJournal: Structure / Year: 2014
Title: Molecular basis of substrate recognition and degradation by human presequence protease.
Authors: King, J.V. / Liang, W.G. / Scherpelz, K.P. / Schilling, A.B. / Meredith, S.C. / Tang, W.J.
History
DepositionNov 1, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 14, 2014Provider: repository / Type: Initial release
Revision 1.1May 21, 2014Group: Database references
Revision 1.2Jul 9, 2014Group: Database references
Revision 1.3Jul 23, 2014Group: Database references
Revision 1.4Mar 26, 2025Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / 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_entry_details.has_protein_modification / _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.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_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.pdbx_leaving_atom_flag / _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: Presequence protease, mitochondrial
B: Beta-amyloid protein 40
C: Beta-amyloid protein 40
D: Presequence protease, mitochondrial
E: Beta-amyloid protein 40
F: Beta-amyloid protein 40
hetero molecules


Theoretical massNumber of molelcules
Total (without water)241,75913
Polymers241,2346
Non-polymers5257
Water72140
1
A: Presequence protease, mitochondrial
B: Beta-amyloid protein 40
C: Beta-amyloid protein 40
hetero molecules


Theoretical massNumber of molelcules
Total (without water)120,9877
Polymers120,7123
Non-polymers2764
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
D: Presequence protease, mitochondrial
E: Beta-amyloid protein 40
F: Beta-amyloid protein 40
hetero molecules


Theoretical massNumber of molelcules
Total (without water)120,7726
Polymers120,5223
Non-polymers2503
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)247.275, 86.183, 158.611
Angle α, β, γ (deg.)90.00, 127.56, 90.00
Int Tables number5
Space group name H-MC121

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Components

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Presequence protease, ... , 2 types, 2 molecules AD

#1: Protein Presequence protease, mitochondrial / hPreP / Pitrilysin metalloproteinase 1 / Metalloprotease 1 / hMP1


Mass: 115762.133 Da / Num. of mol.: 1 / Fragment: UNP residues 33-1037 / Mutation: E107Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KIAA1104, MP1, PITRM1 / Plasmid: pProExH6 / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta(DE3)
References: UniProt: Q5JRX3, Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases
#4: Protein Presequence protease, mitochondrial / Beta-APP40


Mass: 115572.414 Da / Num. of mol.: 1 / Fragment: SEE REMARK 999
Source method: isolated from a genetically manipulated source
Source: (synth.) Homo sapiens (human) / References: UniProt: Q5JRX3

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Beta-amyloid protein ... , 2 types, 4 molecules BECF

#2: Protein/peptide Beta-amyloid protein 40 / Beta-APP40


Mass: 4335.852 Da / Num. of mol.: 2 / Fragment: UNP residues 572-711 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P05067
#3: Protein/peptide Beta-amyloid protein 40 / hPreP / Pitrilysin metalloproteinase 1 / Metalloprotease 1 / hMP1


Mass: 613.749 Da / Num. of mol.: 2 / Fragment: UNP residues 33-1037 / Mutation: E107Q / Source method: obtained synthetically / Source: (gene. exp.) Homo sapiens (human) / Gene: KIAA1104, MP1, PITRM1 / Plasmid: pProExH6 / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta(DE3)
References: Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases

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Non-polymers , 4 types, 47 molecules

#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#7: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3O2
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 40 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationY
Sequence detailsI328V, A397V, AND Q1037R IN CHAINS A AND D ARE NATURAL VARIANTS. CHAINS C AND F ARE IDENTICAL TO ...I328V, A397V, AND Q1037R IN CHAINS A AND D ARE NATURAL VARIANTS. CHAINS C AND F ARE IDENTICAL TO CHAINS B AND E, BUT THE IDENTITIES OF THE MODELED RESIDUES ARE NOT KNOWN.

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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: 2.78 Å3/Da / Density % sol: 55.71 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 15.2% w/v PEG8000, 15 mM TCEP, 80 mM sodium cacodylate, pH 6.5, 160 mM calcium acetate, 20% v/v glycerol, VAPOR DIFFUSION, HANGING DROP, temperature 291.15K

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Data collection

DiffractionMean temperature: 113.5 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 1.045 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 11, 2013
RadiationMonochromator: Rosenbaum-Rock high-resolution double-crystal Si(111)
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.045 Å / Relative weight: 1
ReflectionResolution: 2.7→50 Å / Num. all: 72669 / Num. obs: 67540 / % possible obs: 99.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 2.9 % / Biso Wilson estimate: 36.28 Å2 / Rsym value: 0.18 / Net I/σ(I): 8.69
Reflection shellResolution: 2.7→2.75 Å / Redundancy: 2.4 % / Mean I/σ(I) obs: 1.75 / Num. unique all: 3557 / Rsym value: 0.597 / % possible all: 98.2

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Processing

Software
NameVersionClassification
HKL-3000data collection
PHASERphasing
PHENIX(phenix.refine: 1.8.2_1309)refinement
HKL-3000data reduction
HKL-3000data scaling
RefinementMethod to determine structure: molecular replacement/SAD / Resolution: 2.704→39.621 Å / SU ML: 0.26 / σ(F): 1.34 / Phase error: 24.7 / Stereochemistry target values: MLHL
Details: THE PRESENCE IN THE ASYMMETRIC UNIT OF TWO PROTEINS (CHAINS A AND D) WITH DISTINCT PATTERNS OF SIDE CHAIN MODIFICATION REPRESENTS THE BEST FIT TO THE ELECTRON DENSITY AND IS NOT DERIVED FROM ...Details: THE PRESENCE IN THE ASYMMETRIC UNIT OF TWO PROTEINS (CHAINS A AND D) WITH DISTINCT PATTERNS OF SIDE CHAIN MODIFICATION REPRESENTS THE BEST FIT TO THE ELECTRON DENSITY AND IS NOT DERIVED FROM THE CO-CRYSTALLIZATION OF TWO CHEMICALLY DISTINCT PROTEINS.
RfactorNum. reflection% reflectionSelection details
Rfree0.2323 3724 4.96 %RANDOM
Rwork0.1908 ---
obs0.193 67540 88 %-
all-72669 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 44.63 Å2
Refinement stepCycle: LAST / Resolution: 2.704→39.621 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15966 0 28 40 16034
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00416415
X-RAY DIFFRACTIONf_angle_d1.02422252
X-RAY DIFFRACTIONf_dihedral_angle_d13.1066175
X-RAY DIFFRACTIONf_chiral_restr0.0322419
X-RAY DIFFRACTIONf_plane_restr0.0042879
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.704-2.73790.3193790.22831743X-RAY DIFFRACTION35
2.7379-2.7740.2717960.22511886X-RAY DIFFRACTION37
2.774-2.81190.33341020.22251928X-RAY DIFFRACTION39
2.8119-2.85210.29961040.22362077X-RAY DIFFRACTION41
2.8521-2.89470.31671120.22812095X-RAY DIFFRACTION42
2.8947-2.93990.3051200.22642121X-RAY DIFFRACTION43
2.9399-2.98810.30841190.22022229X-RAY DIFFRACTION44
2.9881-3.03960.34091130.22572261X-RAY DIFFRACTION45
3.0396-3.09480.2751170.21262326X-RAY DIFFRACTION47
3.0948-3.15430.27531380.21512379X-RAY DIFFRACTION48
3.1543-3.21870.28261210.21072455X-RAY DIFFRACTION49
3.2187-3.28860.26221410.20082445X-RAY DIFFRACTION50
3.2886-3.36510.22111270.20252519X-RAY DIFFRACTION50
3.3651-3.44920.23921250.1972561X-RAY DIFFRACTION50
3.4492-3.54240.23251340.19912490X-RAY DIFFRACTION51
3.5424-3.64660.25731270.19262579X-RAY DIFFRACTION51
3.6466-3.76420.23971420.19062556X-RAY DIFFRACTION51
3.7642-3.89860.20931390.19012579X-RAY DIFFRACTION52
3.8986-4.05460.23211310.17382613X-RAY DIFFRACTION52
4.0546-4.23890.22521470.17022645X-RAY DIFFRACTION53
4.2389-4.46210.20711420.16022695X-RAY DIFFRACTION54
4.4621-4.74120.20131430.15212825X-RAY DIFFRACTION57
4.7412-5.10660.19531690.16433089X-RAY DIFFRACTION62
5.1066-5.61920.21151680.19083637X-RAY DIFFRACTION72
5.6192-6.42930.2262150.20584097X-RAY DIFFRACTION82
6.4293-8.08890.22142230.20314372X-RAY DIFFRACTION87
8.0889-39.6250.19352300.18084129X-RAY DIFFRACTION83

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