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- EMDB-21895: Monomer yeast ATP synthase (F1Fo) reconstituted in nanodisc with ... -

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Basic information

Entry
Database: EMDB / ID: EMD-21895
TitleMonomer yeast ATP synthase (F1Fo) reconstituted in nanodisc with inhibitor of bedaquiline bound
Map dataMonomer yeast ATP synthase (F1Fo) reconstituted in nanodisc with inhibitor of bedaquiline bound
Sample
  • Complex: Monomer yeast ATP synthase Fo reconstituted in nanodisc generated in the presence of Bedaquiline
Biological speciesSaccharomyces cerevisiae (brewer's yeast)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsLuo M / Liao MF / Mueller DM
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM66223 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM131731 United States
CitationJournal: Commun Biol / Year: 2020
Title: Bedaquiline inhibits the yeast and human mitochondrial ATP synthases.
Authors: Min Luo / Wenchang Zhou / Hiral Patel / Anurag P Srivastava / Jindrich Symersky / Michał M Bonar / José D Faraldo-Gómez / Maofu Liao / David M Mueller /
Abstract: Bedaquiline (BDQ, Sirturo) has been approved to treat multidrug resistant forms of Mycobacterium tuberculosis. Prior studies suggested that BDQ was a selective inhibitor of the ATP synthase from M. ...Bedaquiline (BDQ, Sirturo) has been approved to treat multidrug resistant forms of Mycobacterium tuberculosis. Prior studies suggested that BDQ was a selective inhibitor of the ATP synthase from M. tuberculosis. However, Sirturo treatment leads to an increased risk of cardiac arrhythmias and death, raising the concern that this adverse effect results from inhibition at a secondary site. Here we show that BDQ is a potent inhibitor of the yeast and human mitochondrial ATP synthases. Single-particle cryo-EM reveals that the site of BDQ inhibition partially overlaps with that of the inhibitor oligomycin. Molecular dynamics simulations indicate that the binding mode of BDQ to this site is similar to that previously seen for a mycobacterial enzyme, explaining the observed lack of selectivity. We propose that derivatives of BDQ ought to be made to increase its specificity toward the mycobacterial enzyme and thereby reduce the side effects for patients that are treated with Sirturo.
History
DepositionMay 2, 2020-
Header (metadata) releaseAug 26, 2020-
Map releaseAug 26, 2020-
UpdateOct 7, 2020-
Current statusOct 7, 2020Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.03
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.03
  • Imaged by UCSF Chimera
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Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21895.png

Downloads & links

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Map

FileDownload / File: emd_21895.map.gz / Format: CCP4 / Size: 122.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMonomer yeast ATP synthase (F1Fo) reconstituted in nanodisc with inhibitor of bedaquiline bound
Voxel sizeX=Y=Z: 1.235 Å
Density
Contour LevelBy AUTHOR: 0.027 / Movie #1: 0.03
Minimum - Maximum-0.095368855 - 0.1788538
Average (Standard dev.)-0.00000695214 (±0.0066427737)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions318318318
Spacing318318318
CellA=B=C: 392.73 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.2351.2351.235
M x/y/z318318318
origin x/y/z0.0000.0000.000
length x/y/z392.730392.730392.730
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ360360360
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS318318318
D min/max/mean-0.0950.179-0.000

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Supplemental data

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Sample components

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Entire : Monomer yeast ATP synthase Fo reconstituted in nanodisc generated...

EntireName: Monomer yeast ATP synthase Fo reconstituted in nanodisc generated in the presence of Bedaquiline
Components
  • Complex: Monomer yeast ATP synthase Fo reconstituted in nanodisc generated in the presence of Bedaquiline

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Supramolecule #1: Monomer yeast ATP synthase Fo reconstituted in nanodisc generated...

SupramoleculeName: Monomer yeast ATP synthase Fo reconstituted in nanodisc generated in the presence of Bedaquiline
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#8
Source (natural)Organism: Saccharomyces cerevisiae (brewer's yeast) / Strain: ATCC 204508 / S288c

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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

Concentration1.5 mg/mL
BufferpH: 8 / Details: 20 mM Tris-HCl, 150 mM NaCl, pH 8.0
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 400 / Support film - Material: CARBON
VitrificationCryogen name: ETHANE / Chamber humidity: 91 %

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Electron microscopy

MicroscopeFEI POLARA 300
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsCalibrated defocus max: 2.8 µm / Calibrated defocus min: 0.8 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.0 mm / Nominal magnification: 31000
Sample stageSpecimen holder model: GATAN LIQUID NITROGEN / Cooling holder cryogen: NITROGEN
TemperatureMin: 80.0 K / Max: 105.0 K
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Number real images: 9258 / Average electron dose: 8.0 e/Å2
Experimental equipment
Model: Tecnai Polara / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1063365
CTF correctionSoftware - Name: RELION (ver. 2)
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION (ver. 2)
Final 3D classificationNumber classes: 6 / Software - Name: RELION (ver. 1.4)
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION (ver. 1.4)
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 2) / Number images used: 122736

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Atomic model buiding 1

Initial modelPDB ID:

6cp3

RefinementSpace: REAL

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