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- PDB-7b3j: Dynamic complex between all-D-enantiomeric peptide D3 with wild-t... -

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Basic information

Entry
Database: PDB / ID: 7b3j
TitleDynamic complex between all-D-enantiomeric peptide D3 with wild-type amyloid precursor protein 672-726 fragment (amyloid beta 1-55)
Components
  • D3 all D-enantimeric peptide
  • Isoform L-APP677 of Amyloid-beta precursor protein
KeywordsPROTEIN BINDING / D-peptide / amyloid-beta / complex / transmembrane
Function / homology
Function and homology information


amyloid-beta complex / growth cone lamellipodium / cellular response to norepinephrine stimulus / collateral sprouting in absence of injury / growth cone filopodium / microglia development / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / regulation of Wnt signaling pathway / axon midline choice point recognition ...amyloid-beta complex / growth cone lamellipodium / cellular response to norepinephrine stimulus / collateral sprouting in absence of injury / growth cone filopodium / microglia development / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / regulation of Wnt signaling pathway / axon midline choice point recognition / regulation of synapse structure or activity / hippocampal neuron apoptotic process / astrocyte activation involved in immune response / NMDA selective glutamate receptor signaling pathway / regulation of spontaneous synaptic transmission / mating behavior / growth factor receptor binding / peptidase activator activity / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / PTB domain binding / positive regulation of amyloid fibril formation / Golgi-associated vesicle / astrocyte projection / neuron remodeling / Lysosome Vesicle Biogenesis / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / nuclear envelope lumen / dendrite development / TRAF6 mediated NF-kB activation / positive regulation of protein metabolic process / signaling receptor activator activity / negative regulation of long-term synaptic potentiation / Advanced glycosylation endproduct receptor signaling / transition metal ion binding / The NLRP3 inflammasome / modulation of excitatory postsynaptic potential / main axon / intracellular copper ion homeostasis / regulation of multicellular organism growth / ECM proteoglycans / response to insulin-like growth factor stimulus / regulation of presynapse assembly / positive regulation of T cell migration / neuronal dense core vesicle / Purinergic signaling in leishmaniasis infection / cellular response to manganese ion / positive regulation of chemokine production / Notch signaling pathway / swimming behavior / neuron projection maintenance / extracellular matrix organization / clathrin-coated pit / positive regulation of mitotic cell cycle / axonogenesis / Mitochondrial protein degradation / positive regulation of calcium-mediated signaling / ionotropic glutamate receptor signaling pathway / platelet alpha granule lumen / astrocyte activation / response to interleukin-1 / regulation of neuron apoptotic process / cellular response to copper ion / cellular response to cAMP / positive regulation of glycolytic process / endosome lumen / trans-Golgi network membrane / positive regulation of interleukin-1 beta production / dendritic shaft / protein serine/threonine kinase binding / positive regulation of long-term synaptic potentiation / learning / central nervous system development / adult locomotory behavior / Post-translational protein phosphorylation / serine-type endopeptidase inhibitor activity / locomotory behavior / microglial cell activation / cellular response to nerve growth factor stimulus / TAK1-dependent IKK and NF-kappa-B activation / positive regulation of non-canonical NF-kappaB signal transduction / synapse organization / visual learning / recycling endosome / regulation of long-term neuronal synaptic plasticity / positive regulation of interleukin-6 production / positive regulation of JNK cascade / Golgi lumen / response to lead ion / cognition / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / cellular response to amyloid-beta / endocytosis / neuron projection development / positive regulation of tumor necrosis factor production / positive regulation of inflammatory response / calcium ion transport / Platelet degranulation / regulation of translation / heparin binding / regulation of gene expression
Similarity search - Function
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, heparin-binding / Amyloid A4 N-terminal heparin-binding / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide ...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, heparin-binding / Amyloid A4 N-terminal heparin-binding / 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, E2 domain / E2 domain superfamily / Amyloidogenic glycoprotein, heparin-binding domain superfamily / E2 domain of amyloid precursor protein / Amyloid precursor protein (APP) E1 domain profile. / Amyloid precursor protein (APP) E2 domain profile. / amyloid A4 / Amyloidogenic glycoprotein / 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
Similarity search - Domain/homology
polypeptide(D) / polypeptide(D) (> 10) / Amyloid-beta precursor protein
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodSOLUTION NMR / molecular dynamics
AuthorsBocharov, E.V. / Volynsky, P.E. / Okhrimenko, I.S. / Urban, A.S.
Funding support Russian Federation, 1items
OrganizationGrant numberCountry
Russian Science Foundation20-64-46027 Russian Federation
CitationJournal: J.Med.Chem. / Year: 2021
Title: All - d - Enantiomeric Peptide D3 Designed for Alzheimer's Disease Treatment Dynamically Interacts with Membrane-Bound Amyloid-beta Precursors.
Authors: Bocharov, E.V. / Gremer, L. / Urban, A.S. / Okhrimenko, I.S. / Volynsky, P.E. / Nadezhdin, K.D. / Bocharova, O.V. / Kornilov, D.A. / Zagryadskaya, Y.A. / Kamynina, A.V. / Kuzmichev, P.K. / ...Authors: Bocharov, E.V. / Gremer, L. / Urban, A.S. / Okhrimenko, I.S. / Volynsky, P.E. / Nadezhdin, K.D. / Bocharova, O.V. / Kornilov, D.A. / Zagryadskaya, Y.A. / Kamynina, A.V. / Kuzmichev, P.K. / Kutzsche, J. / Bolakhrif, N. / Muller-Schiffmann, A. / Dencher, N.A. / Arseniev, A.S. / Efremov, R.G. / Gordeliy, V.I. / Willbold, D.
History
DepositionDec 1, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 13, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 10, 2021Group: Data collection / Database references / Category: citation / database_2 / pdbx_database_proc
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Nov 17, 2021Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 2.0Dec 8, 2021Group: Atomic model / Database references / Category: atom_site / citation
Item: _atom_site.Cartn_x / _atom_site.Cartn_y ..._atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_atom_id / _atom_site.label_atom_id / _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isoform L-APP677 of Amyloid-beta precursor protein
B: D3 all D-enantimeric peptide


Theoretical massNumber of molelcules
Total (without water)7,5982
Polymers7,5982
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: NMR relaxation study, microscale themophoresis
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area850 Å2
ΔGint-1 kcal/mol
Surface area6510 Å2
MethodPISA
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)10 / 10structures with acceptable covalent geometry
RepresentativeModel #1target function

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Components

#1: Protein Isoform L-APP677 of Amyloid-beta precursor protein / APP / ABPP / APPI / Alzheimer disease amyloid protein / Amyloid precursor protein / Amyloid-beta A4 ...APP / ABPP / APPI / Alzheimer disease amyloid protein / Amyloid precursor protein / Amyloid-beta A4 protein / Cerebral vascular amyloid peptide / CVAP / PreA4 / Protease nexin-II / PN-II


Mass: 5991.052 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: APP, A4, AD1 / Plasmid: pGEMEX1 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / Tissue (production host): Cell free expression / References: UniProt: P05067
#2: Polypeptide(D) D3 all D-enantimeric peptide


Mass: 1606.861 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: SOLUTION NMR
NMR experiment
Conditions-IDExperiment-IDSolution-IDSample stateSpectrometer-IDType
115isotropic1H/15N-HSQC
1106isotropic1H/15N-HSQC
196isotropic1H/15N-HSQC
125isotropic21H/15N-TROSY
1127isotropic21H/15N-TROSY
1117isotropic21H/15N-TROSY
135isotropic11H/13C/15N-HNCA
145isotropic11H/13C/15N-HN(CO)CA
155isotropic11H/13C/15N-HNCO
165isotropic21H/13C-(H)CCH-TOCSY
175isotropic113C-edited NOESY-HSQC
185isotropic215N-edited NOESY-HSQC

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Sample preparation

Details
TypeSolution-IDContentsDetails (eV)LabelSolvent system
micelle50.2 mM [U-13C; U-15N] APP672-726, 90% H2O/10% D2OThe APP TM fragments were solubilized in an aqueous suspension of or d38-dodecylphosphocholine micelles under monomeric conditions with the protein/lipid ratio of 1/200.13C_15N90% H2O/10% D2O
micelle60.2 mM [U-13C; U-15N] APP672-726, 0.2 mM D3cys(MTSL), 90% H2O/10% D2OThe APP TM fragments were solubilized in an aqueous suspension of or d38-dodecylphosphocholine micelles under monomeric conditions with the protein/lipid ratio of 1/200.13C_15N90% H2O/10% D2O
micelle70.2 mM [U-13C; U-15N] APP672-726, 0.2 mM (MTSL)cysD3, 90% H2O/10% D2OThe APP TM fragments were solubilized in an aqueous suspension of or d38-dodecylphosphocholine micelles under monomeric conditions with the protein/lipid ratio of 1/200.13C_15N90% H2O/10% D2O
Sample
Conc. (mg/ml)ComponentIsotopic labelingSolution-ID
0.2 mMAPP672-726[U-13C; U-15N]5
0.2 mMAPP672-726[U-13C; U-15N]6
0.2 mMD3cys(MTSL)natural abundance6
0.2 mMAPP672-726[U-13C; U-15N]7
0.2 mM(MTSL)cysD3natural abundance7
Sample conditionsIonic strength: 20 mM / Label: conditions_1 / pH: 6.9 / Pressure: 1 atm / Temperature: 303 K

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NMR measurement

NMR spectrometer
TypeManufacturerModelField strength (MHz)Spectrometer-IDDetails (eV)
Bruker AVANCE IIIBrukerAVANCE III6001Equipped with Cryoprobe
Bruker AVANCE IIIBrukerAVANCE III8002Equipped with Cryoprobe

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Processing

NMR software
NameDeveloperClassification
TopSpinBruker Biospincollection
qMDDKazimierczuk & Orekhovprocessing
CARAKeller and Wuthrichchemical shift assignment
CARAKeller and Wuthrichpeak picking
CYANAGuntert, Mumenthaler and Wuthrichstructure calculation
GROMACSAbraham et alstructure calculation
GROMACSAbraham et alrefinement
RefinementMethod: molecular dynamics / Software ordinal: 7
NMR representativeSelection criteria: target function
NMR ensembleConformer selection criteria: structures with acceptable covalent geometry
Conformers calculated total number: 10 / Conformers submitted total number: 10

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