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- PDB-6wtd: Monomer yeast ATP synthase Fo reconstituted in nanodisc with inhi... -

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Basic information

Entry
Database: PDB / ID: 6wtd
TitleMonomer yeast ATP synthase Fo reconstituted in nanodisc with inhibitor of Bedaquiline bound
Components
  • (ATP synthase subunit ...) x 6
  • ATP synthase protein 8
KeywordsBIOSYNTHETIC PROTEIN / ATP synthase
Function / homology
Function and homology information


: / : / Mitochondrial protein degradation / mitochondrial proton-transporting ATP synthase complex assembly / : / : / : / proton motive force-driven ATP synthesis / proton transmembrane transporter activity / proton transmembrane transport ...: / : / Mitochondrial protein degradation / mitochondrial proton-transporting ATP synthase complex assembly / : / : / : / proton motive force-driven ATP synthesis / proton transmembrane transporter activity / proton transmembrane transport / mitochondrial intermembrane space / protein-containing complex assembly / mitochondrial inner membrane / lipid binding / mitochondrion / identical protein binding / cytosol
Similarity search - Function
ATP synthase, F0 complex, subunit J / ATP synthase protein 8, fungal type / ATP synthase, F0 complex, subunit F, mitochondria, fungi / ATP synthase j chain / Fungal ATP synthase protein 8 (A6L) / Mitochondrial F1-F0 ATP synthase subunit F of fungi / ATP synthase, F0 complex, subunit B/MI25 / ATP synthase, F0 complex, subunit B / Mitochondrial ATP synthase B chain precursor (ATP-synt_B) / ATP synthase, F0 complex, subunit D, mitochondrial ...ATP synthase, F0 complex, subunit J / ATP synthase protein 8, fungal type / ATP synthase, F0 complex, subunit F, mitochondria, fungi / ATP synthase j chain / Fungal ATP synthase protein 8 (A6L) / Mitochondrial F1-F0 ATP synthase subunit F of fungi / ATP synthase, F0 complex, subunit B/MI25 / ATP synthase, F0 complex, subunit B / Mitochondrial ATP synthase B chain precursor (ATP-synt_B) / ATP synthase, F0 complex, subunit D, mitochondrial / ATP synthase D chain, mitochondrial (ATP5H) / ATP synthase, F0 complex, subunit D superfamily, mitochondrial / ATP synthase, F0 complex, subunit A, bacterial/mitochondria / ATP synthase, F0 complex, subunit A / ATP synthase, F0 complex, subunit A, active site / ATP synthase, F0 complex, subunit A superfamily / ATP synthase A chain / ATP synthase a subunit signature. / ATP synthase, F0 complex, subunit C / F1F0 ATP synthase subunit C superfamily / ATP synthase, F0 complex, subunit C, DCCD-binding site / ATP synthase c subunit signature. / V-ATPase proteolipid subunit C-like domain / F/V-ATP synthase subunit C superfamily / ATP synthase subunit C
Similarity search - Domain/homology
ATP synthase subunit a / ATP synthase protein 8 / ATP synthase subunit 4, mitochondrial / ATP synthase subunit d, mitochondrial / ATP synthase subunit 9, mitochondrial / ATP synthase subunit J, mitochondrial / ATP synthase subunit f, mitochondrial
Similarity search - Component
Biological speciesSaccharomyces cerevisiae (brewer's yeast)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.2 Å
AuthorsMueller, D.M. / Srivastava, A.P. / Symersky, J. / Luo, M. / Liao, M.F.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Library of Medicine (NIH/NLM)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, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 26, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 7, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Assembly

Deposited unit
K: ATP synthase subunit 9, mitochondrial
L: ATP synthase subunit 9, mitochondrial
M: ATP synthase subunit 9, mitochondrial
N: ATP synthase subunit 9, mitochondrial
O: ATP synthase subunit 9, mitochondrial
P: ATP synthase subunit 9, mitochondrial
Q: ATP synthase subunit 9, mitochondrial
R: ATP synthase subunit 9, mitochondrial
S: ATP synthase subunit 9, mitochondrial
T: ATP synthase subunit 9, mitochondrial
8: ATP synthase protein 8
X: ATP synthase subunit a
Z: ATP synthase subunit 4, mitochondrial
7: ATP synthase subunit d, mitochondrial
U: ATP synthase subunit f, mitochondrial
J: ATP synthase subunit J, mitochondrial


Theoretical massNumber of molelcules
Total (without water)169,26316
Polymers169,26316
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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ATP synthase subunit ... , 6 types, 15 molecules KLMNOPQRSTXZ7UJ

#1: Protein
ATP synthase subunit 9, mitochondrial / Lipid-binding protein / Oligomycin resistance protein 1


Mass: 7790.385 Da / Num. of mol.: 10 / Source method: isolated from a natural source / Source: (natural) Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: P61829
#3: Protein ATP synthase subunit a


Mass: 27900.430 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: P00854
#4: Protein ATP synthase subunit 4, mitochondrial


Mass: 23194.498 Da / Num. of mol.: 1 / Source method: isolated from a natural source
Source: (natural) Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (yeast)
Strain: ATCC 204508 / S288c / References: UniProt: P05626
#5: Protein ATP synthase subunit d, mitochondrial


Mass: 19709.424 Da / Num. of mol.: 1 / Source method: isolated from a natural source
Source: (natural) Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (yeast)
Strain: ATCC 204508 / S288c / References: UniProt: P30902
#6: Protein ATP synthase subunit f, mitochondrial


Mass: 10584.166 Da / Num. of mol.: 1 / Source method: isolated from a natural source
Source: (natural) Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (yeast)
Strain: ATCC 204508 / S288c / References: UniProt: Q06405
#7: Protein/peptide ATP synthase subunit J, mitochondrial / ATPase synthase I subunit


Mass: 4145.884 Da / Num. of mol.: 1 / Source method: isolated from a natural source
Source: (natural) Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (yeast)
Strain: ATCC 204508 / S288c / References: UniProt: P81450

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Protein/peptide , 1 types, 1 molecules 8

#2: Protein/peptide ATP synthase protein 8


Mass: 5825.215 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: P00856

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Details

Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Monomer yeast ATP synthase Fo reconstituted in nanodisc generated in the presence of Bedaquiline
Type: COMPLEX / Entity ID: all / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Saccharomyces cerevisiae (brewer's yeast) / Strain: ATCC 204508 / S288c
Buffer solutionpH: 8 / Details: 20 mM Tris-HCl, 150 mM NaCl, pH 8.0
SpecimenConc.: 1.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE / Humidity: 91 %

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 36000 X / Calibrated defocus min: 800 nm / Calibrated defocus max: 2800 nm / Cs: 2 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: GATAN LIQUID NITROGEN / Temperature (max): 105 K / Temperature (min): 80 K
Image recordingElectron dose: 8 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of real images: 9258

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Processing

SoftwareName: PHENIX / Version: 1.15.2_3472: / Classification: refinement
EM software
IDNameVersionCategory
1SPIDER13particle selection
2RELION1.4particle selection
3UCSFImage44image acquisition
5RELION2CTF correction
8Coot0.8.1model fitting
10RELION2initial Euler assignment
11RELION1.4final Euler assignment
12RELION1.4classification
13RELION23D reconstruction
14PHENIX1.11.1model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 541568
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 4.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 47169 / Algorithm: BACK PROJECTION / Symmetry type: POINT
Atomic model buildingSpace: REAL
Atomic model buildingPDB-ID: 6CP7

6cp7

Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0079355
ELECTRON MICROSCOPYf_angle_d1.16812678
ELECTRON MICROSCOPYf_dihedral_angle_d12.4325382
ELECTRON MICROSCOPYf_chiral_restr0.0621558
ELECTRON MICROSCOPYf_plane_restr0.0081536

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