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- PDB-7jgb: Cryo-EM structure of bedaquiline-free Mycobacterium smegmatis ATP... -

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Basic information

Entry
Database: PDB / ID: 7jgb
TitleCryo-EM structure of bedaquiline-free Mycobacterium smegmatis ATP synthase FO region
Components
  • ATP synthase subunit a
  • ATP synthase subunit b
  • ATP synthase subunit b-delta
  • ATP synthase subunit c
KeywordsHYDROLASE / Bedaquiline / Sirturo / TMC207 / T207910 / ATP synthase / mycobacteria / tuberculosis
Function / homology
Function and homology information


proton-transporting ATP synthase complex, coupling factor F(o) / membrane => GO:0016020 / proton-transporting ATP synthase activity, rotational mechanism / hydrolase activity / lipid binding / plasma membrane
Similarity search - Function
ATP synthase, F0 complex, subunit b, bacterial / F-type ATP synthase subunit B-like, membrane domain superfamily / : / ATP synthase, F0 complex, subunit A, bacterial/chloroplast / ATP synthase, F0 complex, subunit b/b', bacterial/chloroplast / ATP synthase B/B' CF(0) / ATP synthase, F0 complex, subunit C, bacterial/chloroplast / ATP synthase, F0 complex, subunit A / ATP synthase, F0 complex, subunit A, active site / ATP synthase, F0 complex, subunit A superfamily ...ATP synthase, F0 complex, subunit b, bacterial / F-type ATP synthase subunit B-like, membrane domain superfamily / : / ATP synthase, F0 complex, subunit A, bacterial/chloroplast / ATP synthase, F0 complex, subunit b/b', bacterial/chloroplast / ATP synthase B/B' CF(0) / ATP synthase, F0 complex, subunit C, bacterial/chloroplast / 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. / ATPase, OSCP/delta subunit / ATP synthase delta (OSCP) subunit / 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 b / ATP synthase subunit b-delta / ATP synthase subunit b / ATP synthase subunit c / ATP synthase subunit a / ATP synthase subunit c
Similarity search - Component
Biological speciesMycolicibacterium smegmatis (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsGuo, H. / Courbon, G.M. / Rubinstein, J.L.
Funding support Canada, 2items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR)PJT162186 Canada
Canadian Institutes of Health Research (CIHR)PJT156261 Canada
Citation
Journal: Nature / Year: 2021
Title: Structure of mycobacterial ATP synthase bound to the tuberculosis drug bedaquiline.
Authors: Hui Guo / Gautier M Courbon / Stephanie A Bueler / Juntao Mai / Jun Liu / John L Rubinstein /
Abstract: Tuberculosis-the world's leading cause of death by infectious disease-is increasingly resistant to current first-line antibiotics. The bacterium Mycobacterium tuberculosis (which causes tuberculosis) ...Tuberculosis-the world's leading cause of death by infectious disease-is increasingly resistant to current first-line antibiotics. The bacterium Mycobacterium tuberculosis (which causes tuberculosis) can survive low-energy conditions, allowing infections to remain dormant and decreasing their susceptibility to many antibiotics. Bedaquiline was developed in 2005 from a lead compound identified in a phenotypic screen against Mycobacterium smegmatis. This drug can sterilize even latent M. tuberculosis infections and has become a cornerstone of treatment for multidrug-resistant and extensively drug-resistant tuberculosis. Bedaquiline targets the mycobacterial ATP synthase, which is an essential enzyme in the obligate aerobic Mycobacterium genus, but how it binds the intact enzyme is unknown. Here we determined cryo-electron microscopy structures of M. smegmatis ATP synthase alone and in complex with bedaquiline. The drug-free structure suggests that hook-like extensions from the α-subunits prevent the enzyme from running in reverse, inhibiting ATP hydrolysis and preserving energy in hypoxic conditions. Bedaquiline binding induces large conformational changes in the ATP synthase, creating tight binding pockets at the interface of subunits a and c that explain the potency of this drug as an antibiotic for tuberculosis.
#1: Journal: Biorxiv / Year: 2020
Title: Structure of mycobacterial ATP synthase with the TB drug bedaquiline
Authors: Guo, H. / Courbon, G.M. / Bueler, S.A. / Mai, J. / Liu, J. / Rubinstein, J.L.
History
DepositionJul 18, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 19, 2020Provider: repository / Type: Initial release
Revision 2.0Nov 4, 2020Group: Atomic model / Data collection / Derived calculations
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / em_software / pdbx_struct_assembly_prop
Item: _atom_site_anisotrop.id / _em_software.category ..._atom_site_anisotrop.id / _em_software.category / _em_software.fitting_id / _em_software.imaging_id / _em_software.name / _em_software.version
Revision 2.1Dec 23, 2020Group: Database references / Category: citation / citation_author
Revision 2.2Jan 20, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 2.3Mar 6, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2
Item: _citation.journal_id_ISSN / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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  • Deposited structure unit
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  • EMDB-22320
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Structure viewerMolecule:
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Assembly

Deposited unit
a: ATP synthase subunit a
b: ATP synthase subunit b
d: ATP synthase subunit b-delta
1: ATP synthase subunit c
2: ATP synthase subunit c
3: ATP synthase subunit c
4: ATP synthase subunit c
5: ATP synthase subunit c
6: ATP synthase subunit c
7: ATP synthase subunit c
8: ATP synthase subunit c
9: ATP synthase subunit c


Theoretical massNumber of molelcules
Total (without water)170,09212
Polymers170,09212
Non-polymers00
Water00
1


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

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Components

#1: Protein ATP synthase subunit a / ATP synthase F0 sector subunit a / F-ATPase subunit 6


Mass: 27568.482 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mycolicibacterium smegmatis (bacteria) / References: UniProt: A0R206
#2: Protein ATP synthase subunit b / ATP synthase F(0) sector subunit b / ATPase subunit I / F-type ATPase subunit b / F-ATPase subunit b


Mass: 17636.701 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mycolicibacterium smegmatis (bacteria) / References: UniProt: A0A0D6IV98, UniProt: A0R204*PLUS
#3: Protein ATP synthase subunit b-delta


Mass: 47504.723 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mycolicibacterium smegmatis (bacteria) / References: UniProt: A0R203
#4: Protein
ATP synthase subunit c / ATP synthase F(0) sector subunit c / F-type ATPase subunit c / F-ATPase subunit c / Lipid-binding protein


Mass: 8597.982 Da / Num. of mol.: 9 / Source method: isolated from a natural source / Source: (natural) Mycolicibacterium smegmatis (bacteria) / References: UniProt: Q5TIX5, UniProt: A0R205*PLUS

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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: FO region of ATP synthase from Mycobacterium smegmatis
Type: COMPLEX / Entity ID: all / Source: NATURAL
Molecular weightValue: 0.11 MDa / Experimental value: NO
Source (natural)Organism: Mycolicibacterium smegmatis (bacteria)
Buffer solutionpH: 7.4
SpecimenConc.: 6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER/RHODIUM / Grid type: Homemade
VitrificationInstrument: FEI VITROBOT MARK III / Cryogen name: ETHANE-PROPANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 75000 X / Calibrated defocus min: 800 nm / Calibrated defocus max: 2300 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: ZEMLIN TABLEAU
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 45 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of real images: 7691
Image scansWidth: 4096 / Height: 4096

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Processing

SoftwareName: PHENIX / Version: 1.17.1_3660: / Classification: refinement
EM software
IDNameVersionCategory
2EPUimage acquisition
4cryoSPARC2.11CTF correction
9cryoSPARC2.11model refinement
10cryoSPARC2.11initial Euler assignment
11cryoSPARC2.11final Euler assignment
12cryoSPARC2.11classification
13cryoSPARC2.113D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1435679
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 319756 / Algorithm: BACK PROJECTION / Num. of class averages: 3 / Symmetry type: POINT
Atomic model buildingProtocol: AB INITIO MODEL / Space: RECIPROCAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0077421
ELECTRON MICROSCOPYf_angle_d0.62310087
ELECTRON MICROSCOPYf_dihedral_angle_d12.0321050
ELECTRON MICROSCOPYf_chiral_restr0.0431204
ELECTRON MICROSCOPYf_plane_restr0.0051271

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