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- EMDB-2478: Negative stain electron microscopy structure of compound E-bound ... -

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Basic information

Entry
Database: EMDB / ID: EMD-2478
TitleNegative stain electron microscopy structure of compound E-bound human Presenilin 1 (PS1) complex
Map dataNative human PS1 complex
Sample
  • Sample: Compound E-bound human Presenilin 1 (PS1) complex
  • Protein or peptide: Presenilin-1
  • Protein or peptide: Nicastrin
  • Protein or peptide: Gamma-secretase subunit APH-1A
  • Protein or peptide: Gamma-secretase subunit PEN-2
  • Ligand: E ((S,S)- 2-[2-(3,5-Difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide)
Function / homology
Function and homology information


Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / amyloid precursor protein biosynthetic process / negative regulation of core promoter binding / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / positive regulation of endopeptidase activity / positive regulation of coagulation / positive regulation of amyloid precursor protein biosynthetic process ...Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / amyloid precursor protein biosynthetic process / negative regulation of core promoter binding / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / positive regulation of endopeptidase activity / positive regulation of coagulation / positive regulation of amyloid precursor protein biosynthetic process / Noncanonical activation of NOTCH3 / protein catabolic process at postsynapse / TGFBR3 PTM regulation / sequestering of calcium ion / Notch receptor processing / synaptic vesicle targeting / negative regulation of axonogenesis / central nervous system myelination / membrane protein intracellular domain proteolysis / T cell activation involved in immune response / growth factor receptor binding / skin morphogenesis / choline transport / NOTCH4 Activation and Transmission of Signal to the Nucleus / dorsal/ventral neural tube patterning / regulation of resting membrane potential / neural retina development / myeloid dendritic cell differentiation / L-glutamate import across plasma membrane / Regulated proteolysis of p75NTR / regulation of phosphorylation / metanephros development / locomotion / brain morphogenesis / endoplasmic reticulum calcium ion homeostasis / nuclear outer membrane / amyloid precursor protein metabolic process / regulation of synaptic vesicle cycle / regulation of long-term synaptic potentiation / smooth endoplasmic reticulum calcium ion homeostasis / astrocyte activation involved in immune response / embryonic limb morphogenesis / regulation of canonical Wnt signaling pathway / regulation of postsynapse organization / cell fate specification / skeletal system morphogenesis / aggresome / myeloid cell homeostasis / azurophil granule membrane / glutamate receptor signaling pathway / ciliary rootlet / positive regulation of dendritic spine development / Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases / Golgi cisterna membrane / positive regulation of amyloid fibril formation / G protein-coupled dopamine receptor signaling pathway / positive regulation of receptor recycling / regulation of neuron projection development / protein glycosylation / blood vessel development / adult behavior / mitochondrial transport / amyloid precursor protein catabolic process / heart looping / cerebral cortex cell migration / amyloid-beta formation / membrane protein ectodomain proteolysis / negative regulation of apoptotic signaling pathway / autophagosome assembly / negative regulation of ubiquitin-dependent protein catabolic process / EPH-ephrin mediated repulsion of cells / endopeptidase activator activity / neuron development / somitogenesis / smooth endoplasmic reticulum / hematopoietic progenitor cell differentiation / Nuclear signaling by ERBB4 / calcium ion homeostasis / T cell proliferation / regulation of synaptic transmission, glutamatergic / rough endoplasmic reticulum / Notch signaling pathway / Degradation of the extracellular matrix / neuron projection maintenance / NOTCH2 Activation and Transmission of Signal to the Nucleus / cerebellum development / cellular response to calcium ion / NRIF signals cell death from the nucleus / Activated NOTCH1 Transmits Signal to the Nucleus / post-embryonic development / dendritic shaft / thymus development / positive regulation of glycolytic process / epithelial cell proliferation / PDZ domain binding / astrocyte activation / NOTCH3 Activation and Transmission of Signal to the Nucleus / apoptotic signaling pathway / synapse organization / neuron migration
Similarity search - Function
Peptidase A22A, presenilin 1 / Gamma-secretase subunit Aph-1 / Gamma-secretase aspartyl protease complex, presenilin enhancer-2 subunit / Aph-1 protein / Presenilin enhancer-2 subunit of gamma secretase / Peptidase A22A, presenilin / Presenilin, C-terminal / Presenilin / Nicastrin / Nicastrin, small lobe ...Peptidase A22A, presenilin 1 / Gamma-secretase subunit Aph-1 / Gamma-secretase aspartyl protease complex, presenilin enhancer-2 subunit / Aph-1 protein / Presenilin enhancer-2 subunit of gamma secretase / Peptidase A22A, presenilin / Presenilin, C-terminal / Presenilin / Nicastrin / Nicastrin, small lobe / Nicastrin large lobe / Nicastrin small lobe / Presenilin/signal peptide peptidase / Presenilin, signal peptide peptidase, family
Similarity search - Domain/homology
Presenilin-1 / Nicastrin / Gamma-secretase subunit APH-1A / Gamma-secretase subunit PEN-2
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / negative staining / Resolution: 17.4 Å
AuthorsLi Y / Lu S / Tsai CJ / Bohm C / Qamar S / Dodd RB / Meadows W / Jeon A / McLeod A / Chen F ...Li Y / Lu S / Tsai CJ / Bohm C / Qamar S / Dodd RB / Meadows W / Jeon A / McLeod A / Chen F / Arimon M / Berezovska O / Hyman BT / Tomita T / Iwatsubod T / Johnsof CM / Farrer L / Schmitt-Ulms G / Fraser P / St George-Hyslop P
CitationJournal: Structure / Year: 2014
Title: Structural interactions between inhibitor and substrate docking sites give insight into mechanisms of human PS1 complexes.
Authors: Yi Li / Stephen Hsueh-Jeng Lu / Ching-Ju Tsai / Christopher Bohm / Seema Qamar / Roger B Dodd / William Meadows / Amy Jeon / Adam McLeod / Fusheng Chen / Muriel Arimon / Oksana Berezovska / ...Authors: Yi Li / Stephen Hsueh-Jeng Lu / Ching-Ju Tsai / Christopher Bohm / Seema Qamar / Roger B Dodd / William Meadows / Amy Jeon / Adam McLeod / Fusheng Chen / Muriel Arimon / Oksana Berezovska / Bradley T Hyman / Taisuke Tomita / Takeshi Iwatsubo / Christopher M Johnson / Lindsay A Farrer / Gerold Schmitt-Ulms / Paul E Fraser / Peter H St George-Hyslop /
Abstract: Presenilin-mediated endoproteolysis of transmembrane proteins plays a key role in physiological signaling and in the pathogenesis of Alzheimer disease and some cancers. Numerous inhibitors have been ...Presenilin-mediated endoproteolysis of transmembrane proteins plays a key role in physiological signaling and in the pathogenesis of Alzheimer disease and some cancers. Numerous inhibitors have been found via library screens, but their structural mechanisms remain unknown. We used several biophysical techniques to investigate the structure of human presenilin complexes and the effects of peptidomimetic γ-secretase inhibitors. The complexes are bilobed. The head contains nicastrin ectodomain. The membrane-embedded base has a central channel and a lateral cleft, which may represent the initial substrate docking site. Inhibitor binding induces widespread structural changes, including rotation of the head and closure of the lateral cleft. These changes block substrate access to the catalytic pocket and inhibit the enzyme. Intriguingly, peptide substrate docking has reciprocal effects on the inhibitor binding site. Similar reciprocal shifts may underlie the mechanisms of other inhibitors and of the "lateral gate" through which substrates access to the catalytic site.
History
DepositionSep 23, 2013-
Header (metadata) releaseNov 13, 2013-
Map releaseNov 20, 2013-
UpdateMar 2, 2016-
Current statusMar 2, 2016Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0155
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by radius
  • Surface level: 0.0155
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

EMD-2478.png

Downloads & links

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Map

FileDownload / File: emd_2478.map.gz / Format: CCP4 / Size: 7.8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationNative human PS1 complex
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
2.04 Å/pix.
x 128 pix.
= 261.12 Å		2.04 Å/pix.
x 128 pix.
= 261.12 Å		2.04 Å/pix.
x 128 pix.
= 261.12 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 2.04 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0155 / Movie #1: 0.0155
Minimum - Maximum-0.0298597 - 0.05378654
Average (Standard dev.)-0.00013971 (±0.00514203)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions128128128
Spacing128128128
CellA=B=C: 261.12 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z2.042.042.04
M x/y/z128128128
origin x/y/z0.0000.0000.000
length x/y/z261.120261.120261.120
α/β/γ90.00090.00090.000
start NX/NY/NZ00-40
NX/NY/NZ555581
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS128128128
D min/max/mean-0.0300.054-0.000

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Supplemental data

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Sample components

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Entire : Compound E-bound human Presenilin 1 (PS1) complex

EntireName: Compound E-bound human Presenilin 1 (PS1) complex
Components
  • Sample: Compound E-bound human Presenilin 1 (PS1) complex
  • Protein or peptide: Presenilin-1
  • Protein or peptide: Nicastrin
  • Protein or peptide: Gamma-secretase subunit APH-1A
  • Protein or peptide: Gamma-secretase subunit PEN-2
  • Ligand: E ((S,S)- 2-[2-(3,5-Difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide)

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Supramolecule #1000: Compound E-bound human Presenilin 1 (PS1) complex

SupramoleculeName: Compound E-bound human Presenilin 1 (PS1) complex / type: sample / ID: 1000 / Details: The sample was monodisperse / Oligomeric state: 1:1:1:1 / Number unique components: 5
Molecular weightTheoretical: 200 KDa

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Macromolecule #1: Presenilin-1

MacromoleculeName: Presenilin-1 / type: protein_or_peptide / ID: 1 / Name.synonym: Protein S182
Details: N-terminus as tagged with TAP tag composed of Protein G and Streptavidin binding peptide tags separated by tobacco etch virus protease cleavage site
Number of copies: 1 / Recombinant expression: Yes
Source (natural)Organism: Homo sapiens (human) / synonym: Human
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HEK293
SequenceUniProtKB: Presenilin-1

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Macromolecule #2: Nicastrin

MacromoleculeName: Nicastrin / type: protein_or_peptide / ID: 2 / Name.synonym: KIAA0253 / Number of copies: 1 / Recombinant expression: No
Source (natural)Organism: Homo sapiens (human) / synonym: Human / Cell: HEK293
SequenceUniProtKB: Nicastrin

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Macromolecule #3: Gamma-secretase subunit APH-1A

MacromoleculeName: Gamma-secretase subunit APH-1A / type: protein_or_peptide / ID: 3 / Name.synonym: Aph-1alpha / Number of copies: 1 / Recombinant expression: No
Source (natural)Organism: Homo sapiens (human) / synonym: Human / Cell: HEK293
SequenceUniProtKB: Gamma-secretase subunit APH-1A

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Macromolecule #4: Gamma-secretase subunit PEN-2

MacromoleculeName: Gamma-secretase subunit PEN-2 / type: protein_or_peptide / ID: 4 / Name.synonym: Presenilin enhancer protein 2 / Number of copies: 1 / Recombinant expression: No
Source (natural)Organism: Homo sapiens (human) / synonym: Human / Cell: HEK293
SequenceUniProtKB: Gamma-secretase subunit PEN-2

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Macromolecule #5: E ((S,S)- 2-[2-(3,5-Difluorophenyl)-acetylamino]-N-(1-methyl-2-ox...

MacromoleculeName: E ((S,S)- 2-[2-(3,5-Difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide)
type: ligand / ID: 5 / Name.synonym: gamma-Secretase Inhibitor XXI / Number of copies: 1 / Recombinant expression: No
Source (natural)Organism: synthetic construct (others)

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Experimental details

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Structure determination

Methodnegative staining
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.02 mg/mL
BufferpH: 7.4
Details: 50 mM Tris-HCl, 150 mM NaCl, 2 mM EDTA, 5 mM MgCl2, 5 mM CaCl2
StainingType: NEGATIVE
Details: Grids with adsorbed protein floated on 1% w/v uranyl acetate for 2-10 seconds
GridDetails: Carbon-coated 400-mesh copper grids were glow discharged in air at 600-700 V for 30-60 seconds on an Edward S150B sputter coater.
VitrificationCryogen name: NONE / Instrument: OTHER

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Electron microscopy

MicroscopeFEI TECNAI 12
DateSep 19, 2009
Image recordingCategory: CCD / Film or detector model: TVIPS TEMCAM-F224 (2k x 2k) / Number real images: 300
Electron beamAcceleration voltage: 120 kV / Electron source: TUNGSTEN HAIRPIN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2 mm / Nominal defocus max: 1.0 µm
Sample stageSpecimen holder model: OTHER

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Image processing

DetailsThe particles were selected using EMAN2
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Algorithm: OTHER / Resolution.type: BY AUTHOR / Resolution: 17.4 Å / Resolution method: OTHER / Software - Name: EMAN2, RELION / Number images used: 10651

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