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- PDB-7b3k: Dynamic complex between all-D-enantiomeric peptide D3 with L723P ... -

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Basic information

Entry
Database: PDB / ID: 7b3k
TitleDynamic complex between all-D-enantiomeric peptide D3 with L723P mutant of amyloid precursor protein (APP) 672-726 fragment (amyloid beta 1-55)
Components
  • D3 all D-enantimeric peptide
  • Isoform L-APP677 of Amyloid-beta precursor protein
KeywordsPROTEIN BINDING / D3-peptide / all-D-enantiomeric peptide / Australian mutation / amyloid-beta / amyloid precursor protein / complex / transmembrane
Function / homology
Function and homology information


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 / axo-dendritic transport / synaptic assembly at neuromuscular junction / smooth endoplasmic reticulum calcium ion homeostasis ...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 / 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 / ciliary rootlet / Lysosome Vesicle Biogenesis / PTB domain binding / Golgi-associated vesicle / positive regulation of amyloid fibril formation / neuron remodeling / 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 / modulation of excitatory postsynaptic potential / suckling behavior / COPII-coated ER to Golgi transport vesicle / dendrite development / smooth endoplasmic reticulum / regulation of NMDA receptor activity / TRAF6 mediated NF-kB activation / 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 long-term synaptic potentiation / 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 / forebrain development / regulation of peptidyl-tyrosine phosphorylation / positive regulation of chemokine production / clathrin-coated pit / Notch signaling pathway / positive regulation of G2/M transition of mitotic cell cycle / ionotropic glutamate receptor signaling pathway / positive regulation of protein metabolic process / neuron projection maintenance / cholesterol metabolic process / extracellular matrix organization / positive regulation of glycolytic 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 / central nervous system development / positive regulation of interleukin-1 beta production / positive regulation of long-term synaptic potentiation / astrocyte activation / endosome lumen / synapse organization / Post-translational protein phosphorylation / regulation of long-term neuronal synaptic plasticity / positive regulation of JNK cascade / microglial cell activation / TAK1-dependent IKK and NF-kappa-B activation / visual learning / neuromuscular junction / serine-type endopeptidase inhibitor activity / recycling endosome / cognition / positive regulation of inflammatory response / Golgi lumen / neuron cellular homeostasis / endocytosis / positive regulation of interleukin-6 production / positive regulation of non-canonical NF-kappaB signal transduction / cellular response to amyloid-beta / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / neuron projection development / positive regulation of DNA-binding transcription factor activity / G2/M transition of mitotic cell cycle / cell-cell junction / synaptic vesicle / positive regulation of tumor necrosis factor production / regulation of translation
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, 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 ...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. / 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 / 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 / citation_author ...citation / citation_author / 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 / _citation_author.name / _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
Revision 2.1Jun 14, 2023Group: Other / Category: pdbx_database_status / Item: _pdbx_database_status.status_code_nmr_data

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)7,5822
Polymers7,5822
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: NMR relaxation study, microscale themophoresis
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area990 Å2
ΔGint1 kcal/mol
Surface area6100 Å2
MethodPISA
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)8 / 8structures with the least restraint violations
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: 5975.009 Da / Num. of mol.: 1 / Mutation: V52P
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) / 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
111isotropic1H/15N-HSQC
1102isotropic1H/15N-HSQC
121isotropic21H/15N-TROSY
1122isotropic21H/15N-TROSY
131isotropic11H/13C/15N-HNCA
141isotropic11H/13C/15N-HN(CO)CA
151isotropic11H/13C/15N-HNCO
171isotropic21H/13C-(H)CCH-TOCSY
161isotropic113C-edited NOESY-HSQC
181isotropic215N-edited NOESY-HSQC

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Sample preparation

Details
TypeSolution-IDContentsDetailsLabelSolvent system
micelle10.2 mM [U-13C; U-15N] APP_L723P_672-726, 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
micelle20.2 mM [U-13C; U-15N] APP_L723P_672-726, 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
Sample
Conc. (mg/ml)ComponentIsotopic labelingSolution-ID
0.2 mMAPP_L723P_672-726[U-13C; U-15N]1
0.2 mMAPP_L723P_672-726[U-13C; U-15N]2
0.2 mMD3cys(MTSL)natural abundance2
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
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 the least restraint violations
Conformers calculated total number: 8 / Conformers submitted total number: 8

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