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- EMDB-23765: The F1 region of inhibitor-free Saccharomyces cerevisiae ATP synthase -

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Basic information

Entry
Database: EMDB / ID: EMD-23765
TitleThe F1 region of inhibitor-free Saccharomyces cerevisiae ATP synthase
Map dataGlobally sharpened map.
Sample
  • Complex: The F1 region of inhibitor-free Saccharomyces cerevisiae ATP synthase
Function / homology
Function and homology information


mitochondrial proton-transporting ATP synthase, central stalk / mitochondrial proton-transporting ATP synthase complex / proton motive force-driven mitochondrial ATP synthesis / proton motive force-driven ATP synthesis / proton-transporting ATP synthase complex, catalytic core F(1) / H+-transporting two-sector ATPase / proton-transporting ATPase activity, rotational mechanism / proton-transporting ATP synthase activity, rotational mechanism / mitochondrial inner membrane / ATP hydrolysis activity ...mitochondrial proton-transporting ATP synthase, central stalk / mitochondrial proton-transporting ATP synthase complex / proton motive force-driven mitochondrial ATP synthesis / proton motive force-driven ATP synthesis / proton-transporting ATP synthase complex, catalytic core F(1) / H+-transporting two-sector ATPase / proton-transporting ATPase activity, rotational mechanism / proton-transporting ATP synthase activity, rotational mechanism / mitochondrial inner membrane / ATP hydrolysis activity / mitochondrion / ATP binding
Similarity search - Function
ATP synthase, F1 complex, epsilon subunit, mitochondrial / ATP synthase, F1 complex, epsilon subunit superfamily, mitochondrial / Mitochondrial ATP synthase epsilon chain / ATP synthase, F1 complex, gamma subunit conserved site / ATP synthase gamma subunit signature. / ATP synthase, F1 complex, beta subunit / ATP synthase, alpha subunit, C-terminal domain superfamily / ATP synthase, F1 complex, gamma subunit / ATP synthase, F1 complex, gamma subunit superfamily / ATP synthase ...ATP synthase, F1 complex, epsilon subunit, mitochondrial / ATP synthase, F1 complex, epsilon subunit superfamily, mitochondrial / Mitochondrial ATP synthase epsilon chain / ATP synthase, F1 complex, gamma subunit conserved site / ATP synthase gamma subunit signature. / ATP synthase, F1 complex, beta subunit / ATP synthase, alpha subunit, C-terminal domain superfamily / ATP synthase, F1 complex, gamma subunit / ATP synthase, F1 complex, gamma subunit superfamily / ATP synthase / ATP synthase, alpha subunit, C-terminal / ATP synthase, F1 complex, alpha subunit / ATP synthase, F1 complex, alpha subunit nucleotide-binding domain / ATP synthase alpha/beta chain, C terminal domain / ATPase, F1/V1 complex, beta/alpha subunit, C-terminal / ATP synthase subunit alpha, N-terminal domain-like superfamily / ATPase, F1/V1/A1 complex, alpha/beta subunit, N-terminal domain superfamily / ATPase, F1/V1/A1 complex, alpha/beta subunit, N-terminal domain / ATP synthase alpha/beta family, beta-barrel domain / ATPase, alpha/beta subunit, nucleotide-binding domain, active site / ATP synthase alpha and beta subunits signature. / ATPase, F1/V1/A1 complex, alpha/beta subunit, nucleotide-binding domain / ATP synthase alpha/beta family, nucleotide-binding domain / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
ATP synthase subunit beta / ATP synthase subunit gamma / ATP synthase subunit alpha / ATP synthase subunit epsilon, mitochondrial
Similarity search - Component
Biological speciesSaccharomyces cerevisiae (brewer's yeast)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.2 Å
AuthorsGuo H / Rubinstein JL
Funding support Canada, United States, 8 items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR)PJT162186 Canada
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM092218 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R01 CA226833 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35 GM133552 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)K23 HL138291 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)T32 GM065086 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)T32 GM007347 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)F30 CA236131 United States
CitationJournal: Nat Chem Biol / Year: 2022
Title: Apoptolidin family glycomacrolides target leukemia through inhibition of ATP synthase.
Authors: Benjamin J Reisman / Hui Guo / Haley E Ramsey / Madison T Wright / Bradley I Reinfeld / P Brent Ferrell / Gary A Sulikowski / W Kimryn Rathmell / Michael R Savona / Lars Plate / John L ...Authors: Benjamin J Reisman / Hui Guo / Haley E Ramsey / Madison T Wright / Bradley I Reinfeld / P Brent Ferrell / Gary A Sulikowski / W Kimryn Rathmell / Michael R Savona / Lars Plate / John L Rubinstein / Brian O Bachmann /
Abstract: Cancer cells have long been recognized to exhibit unique bioenergetic requirements. The apoptolidin family of glycomacrolides are distinguished by their selective cytotoxicity towards oncogene- ...Cancer cells have long been recognized to exhibit unique bioenergetic requirements. The apoptolidin family of glycomacrolides are distinguished by their selective cytotoxicity towards oncogene-transformed cells, yet their molecular mechanism remains uncertain. We used photoaffinity analogs of the apoptolidins to identify the F subcomplex of mitochondrial ATP synthase as the target of apoptolidin A. Cryogenic electron microscopy (cryo-EM) of apoptolidin and ammocidin-ATP synthase complexes revealed a novel shared mode of inhibition that was confirmed by deep mutational scanning of the binding interface to reveal resistance mutations which were confirmed using CRISPR-Cas9. Ammocidin A was found to suppress leukemia progression in vivo at doses that were tolerated with minimal toxicity. The combination of cellular, structural, mutagenesis, and in vivo evidence defines the mechanism of action of apoptolidin family glycomacrolides and establishes a path to address oxidative phosphorylation-dependent cancers.
History
DepositionApr 3, 2021-
Header (metadata) releaseAug 11, 2021-
Map releaseAug 11, 2021-
UpdateAug 11, 2021-
Current statusAug 11, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.55
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 0.55
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23765.png

Downloads & links

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Map

FileDownload / File: emd_23765.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationGlobally sharpened map.
Voxel sizeX=Y=Z: 1.45 Å
Density
Contour LevelBy AUTHOR: 0.55 / Movie #1: 0.55
Minimum - Maximum-0.6568412 - 1.9609759
Average (Standard dev.)0.0007128328 (±0.07470291)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 371.2 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.451.451.45
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z371.200371.200371.200
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ400400400
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.6571.9610.001

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Supplemental data

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Mask #1

Fileemd_23765_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Unsharpened map.

Fileemd_23765_additional_1.map
AnnotationUnsharpened map.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 1.

Fileemd_23765_half_map_1.map
AnnotationHalf map 1.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 2.

Fileemd_23765_half_map_2.map
AnnotationHalf map 2.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : The F1 region of inhibitor-free Saccharomyces cerevisiae ATP synthase

EntireName: The F1 region of inhibitor-free Saccharomyces cerevisiae ATP synthase
Components
  • Complex: The F1 region of inhibitor-free Saccharomyces cerevisiae ATP synthase

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Supramolecule #1: The F1 region of inhibitor-free Saccharomyces cerevisiae ATP synthase

SupramoleculeName: The F1 region of inhibitor-free Saccharomyces cerevisiae ATP synthase
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Saccharomyces cerevisiae (brewer's yeast) / Strain: USY006
Molecular weightTheoretical: 400 KDa

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration15 mg/mL
BufferpH: 7.4
GridModel: Homemade / Material: COPPER/RHODIUM / Mesh: 400 / Support film - Material: GOLD / Support film - topology: HOLEY / Support film - Film thickness: 30.0 nm / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE-PROPANE / Chamber humidity: 100 % / Chamber temperature: 4 K / Instrument: FEI VITROBOT MARK III

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Electron microscopy

MicroscopeFEI TECNAI F20
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 30.0 µm / Calibrated defocus max: 3.2 µm / Calibrated magnification: 34483 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.0 mm / Nominal defocus min: 1.0 µm / Nominal magnification: 25000
Sample stageSpecimen holder model: GATAN 626 SINGLE TILT LIQUID NITROGEN CRYO TRANSFER HOLDER
Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Digitization - Dimensions - Width: 3710 pixel / Digitization - Dimensions - Height: 3838 pixel / Number grids imaged: 1 / Number real images: 190 / Average exposure time: 15.0 sec. / Average electron dose: 36.0 e/Å2
Experimental equipment
Model: Tecnai F20 / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 38514
CTF correctionSoftware - Name: cryoSPARC (ver. 2.15)
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: cryoSPARC (ver. 2.15)
Final 3D classificationNumber classes: 3 / Avg.num./class: 11345 / Software - Name: cryoSPARC (ver. 2.15)
Final angle assignmentType: PROJECTION MATCHING / Software - Name: cryoSPARC (ver. 2.15)
Final reconstructionNumber classes used: 3 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: BACK PROJECTION / Resolution.type: BY AUTHOR / Resolution: 4.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 2.15) / Number images used: 34035
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: RECIPROCAL / Protocol: AB INITIO MODEL

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