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- PDB-7jga: Cryo-EM structure of bedaquiline-saturated Mycobacterium smegmati... -

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Basic information

Entry
Database: PDB / ID: 7jga
TitleCryo-EM structure of bedaquiline-saturated Mycobacterium smegmatis ATP synthase rotational state 3
Components(ATP synthase ...) x 8
KeywordsHYDROLASE / Bedaquiline / Sirturo / TMC207 / T207910 / ATP synthase / mycobacteria / tuberculosis
Function / homology
Function and homology information


proton motive force-driven plasma membrane ATP synthesis / : / : / membrane => GO:0016020 / H+-transporting two-sector ATPase / proton-transporting ATPase activity, rotational mechanism / proton-transporting ATP synthase activity, rotational mechanism / ADP binding / hydrolase activity / lipid binding ...proton motive force-driven plasma membrane ATP synthesis / : / : / membrane => GO:0016020 / H+-transporting two-sector ATPase / proton-transporting ATPase activity, rotational mechanism / proton-transporting ATP synthase activity, rotational mechanism / ADP binding / hydrolase activity / lipid binding / ATP hydrolysis activity / ATP binding / plasma membrane
Similarity search - Function
ATP Synthase; domain 1 / F0F1 ATP synthase delta/epsilon subunit, N-terminal / ATP synthase alpha/beta chain, C-terminal domain / Lysin / F1F0 ATP synthase subunit C / F1FO ATP Synthase / Elongation Factor Tu (Ef-tu); domain 3 - #20 / ATP synthase, F0 complex, subunit b, bacterial / F-type ATP synthase subunit B-like, membrane domain superfamily / : ...ATP Synthase; domain 1 / F0F1 ATP synthase delta/epsilon subunit, N-terminal / ATP synthase alpha/beta chain, C-terminal domain / Lysin / F1F0 ATP synthase subunit C / F1FO ATP Synthase / Elongation Factor Tu (Ef-tu); domain 3 - #20 / 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, F1 complex, delta/epsilon subunit / ATP synthase, F1 complex, delta/epsilon subunit, N-terminal / F0F1 ATP synthase delta/epsilon subunit, N-terminal / ATP synthase, Delta/Epsilon chain, beta-sandwich domain / 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. / 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 / V-ATPase proteolipid subunit C-like domain / F/V-ATP synthase subunit C superfamily / ATP synthase subunit C / : / ATPase, F1/V1 complex, beta/alpha subunit, C-terminal / C-terminal domain of V and A type ATP synthase / 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 / Elongation Factor Tu (Ef-tu); domain 3 / P-loop containing nucleotide triphosphate hydrolases / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / Up-down Bundle / Beta Barrel / Sandwich / P-loop containing nucleoside triphosphate hydrolase / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / ADENOSINE-5'-TRIPHOSPHATE / Bedaquiline / PHOSPHATE ION / ATP synthase epsilon chain / ATP synthase subunit beta / ATP synthase gamma chain / ATP synthase subunit alpha / ATP synthase subunit b / ATP synthase epsilon chain ...ADENOSINE-5'-DIPHOSPHATE / ADENOSINE-5'-TRIPHOSPHATE / Bedaquiline / PHOSPHATE ION / ATP synthase epsilon chain / ATP synthase subunit beta / ATP synthase gamma chain / ATP synthase subunit alpha / ATP synthase subunit b / ATP synthase epsilon chain / ATP synthase subunit beta / ATP synthase gamma chain / ATP synthase subunit alpha / 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: 3.2 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 1.1Dec 23, 2020Group: Database references / Category: citation / citation_author
Revision 1.2Jan 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 1.3Mar 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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Assembly

Deposited unit
A: ATP synthase subunit alpha
B: ATP synthase subunit alpha
C: ATP synthase subunit alpha
D: ATP synthase subunit beta
E: ATP synthase subunit beta
F: ATP synthase subunit beta
G: ATP synthase gamma chain
H: ATP synthase epsilon chain
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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)554,70536
Polymers548,67520
Non-polymers6,02916
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area92860 Å2
ΔGint-764 kcal/mol
Surface area156720 Å2

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Components

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ATP synthase ... , 8 types, 20 molecules ABCDEFGHabd123456789

#1: Protein ATP synthase subunit alpha / ATP synthase F1 sector subunit alpha / F-ATPase subunit alpha


Mass: 58951.461 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Source: (natural) Mycolicibacterium smegmatis (bacteria)
References: UniProt: A0A0D6IV93, UniProt: A0R202*PLUS, H+-transporting two-sector ATPase
#2: Protein ATP synthase subunit beta / ATP synthase F1 sector subunit beta / F-ATPase subunit beta


Mass: 51670.453 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Source: (natural) Mycolicibacterium smegmatis (bacteria)
References: UniProt: A0A0D6IU77, UniProt: A0R200*PLUS, H+-transporting two-sector ATPase
#3: Protein ATP synthase gamma chain / ATP synthase F1 sector gamma subunit / F-ATPase gamma subunit


Mass: 33439.836 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mycolicibacterium smegmatis (bacteria) / References: UniProt: A0A0D6IUE3, UniProt: A0R201*PLUS
#4: Protein ATP synthase epsilon chain / ATP synthase F1 sector epsilon subunit / F-ATPase epsilon subunit


Mass: 13277.741 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mycolicibacterium smegmatis (bacteria) / References: UniProt: A0A0D6IU73, UniProt: A0R1Z9*PLUS
#5: 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
#6: 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
#7: 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
#8: 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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Non-polymers , 5 types, 16 molecules

#9: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Comment: ATP, energy-carrying molecule*YM
#10: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#11: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#12: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#13: Chemical
ChemComp-BQ1 / Bedaquiline


Mass: 555.505 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C32H31BrN2O2 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, antibiotic*YM

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Details

Has ligand of interestY

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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: ATP synthase from Mycobacterium smegmatis / Type: COMPLEX / Entity ID: #1-#8 / Source: NATURAL
Molecular weightValue: 0.55 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: 600 nm / Calibrated defocus max: 3000 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: 41 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of real images: 7589
Image scansWidth: 4096 / Height: 4096

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Processing

EM software
IDNameVersionCategory
2EPUimage acquisition
4cryoSPARC2.13CTF correction
9cryoSPARC2.13initial Euler assignment
10cryoSPARC2.13final Euler assignment
11cryoSPARC2.13classification
12cryoSPARC2.133D reconstruction
13cryoSPARC2.13model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1825672
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 155488 / Algorithm: BACK PROJECTION / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: AB INITIO MODEL / Space: RECIPROCAL

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