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- PDB-8g0b: Cryo-EM structure of TBAJ-876-bound Mycobacterium smegmatis ATP s... -

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Basic information

Entry
Database: PDB / ID: 8g0b
TitleCryo-EM structure of TBAJ-876-bound Mycobacterium smegmatis ATP synthase FO region
Components
  • ATP synthase subunit a
  • ATP synthase subunit b
  • ATP synthase subunit b-delta
  • ATP synthase subunit c
KeywordsTRANSLOCASE/INHIBITOR / ATP synthase / mycobacterial / inhibitor / tuberculosis / antibiotic / HYDROLASE / TRANSLOCASE-INHIBITOR complex
Function / homology
Function and homology information


proton-transporting ATP synthase complex, coupling factor F(o) / 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
Chem-YGR / ATP synthase subunit b-delta / ATP synthase subunit b / ATP synthase subunit c / ATP synthase subunit a
Similarity search - Component
Biological speciesMycolicibacterium smegmatis MC2 155 (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsCourbon, G.M. / Rubinstein, J.L.
Funding support Canada, 1items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR)PJT162186 Canada
CitationJournal: EMBO J / Year: 2023
Title: Mechanism of mycobacterial ATP synthase inhibition by squaramides and second generation diarylquinolines.
Authors: Gautier M Courbon / Paul R Palme / Lea Mann / Adrian Richter / Peter Imming / John L Rubinstein /
Abstract: Mycobacteria, such as Mycobacterium tuberculosis, depend on the activity of adenosine triphosphate (ATP) synthase for growth. The diarylquinoline bedaquiline (BDQ), a mycobacterial ATP synthase ...Mycobacteria, such as Mycobacterium tuberculosis, depend on the activity of adenosine triphosphate (ATP) synthase for growth. The diarylquinoline bedaquiline (BDQ), a mycobacterial ATP synthase inhibitor, is an important medication for treatment of drug-resistant tuberculosis but suffers from off-target effects and is susceptible to resistance mutations. Consequently, both new and improved mycobacterial ATP synthase inhibitors are needed. We used electron cryomicroscopy and biochemical assays to study the interaction of Mycobacterium smegmatis ATP synthase with the second generation diarylquinoline TBAJ-876 and the squaramide inhibitor SQ31f. The aryl groups of TBAJ-876 improve binding compared with BDQ, while SQ31f, which blocks ATP synthesis ~10 times more potently than ATP hydrolysis, binds a previously unknown site in the enzyme's proton-conducting channel. Remarkably, BDQ, TBAJ-876, and SQ31f all induce similar conformational changes in ATP synthase, suggesting that the resulting conformation is particularly suited for drug binding. Further, high concentrations of the diarylquinolines uncouple the transmembrane proton motive force while for SQ31f they do not, which may explain why high concentrations of diarylquinolines, but not SQ31f, have been reported to kill mycobacteria.
History
DepositionJan 31, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 15, 2023Provider: repository / Type: Initial release
Revision 1.1Jul 12, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Aug 9, 2023Group: Database references / Category: citation / Item: _citation.journal_volume
Revision 1.3Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
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
a: ATP synthase subunit a
b: ATP synthase subunit b
d: ATP synthase subunit b-delta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)174,69519
Polymers170,09212
Non-polymers4,6037
Water00
1


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

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Components

#1: Protein
ATP synthase subunit c


Mass: 8597.982 Da / Num. of mol.: 9 / Source method: isolated from a natural source
Source: (natural) Mycolicibacterium smegmatis MC2 155 (bacteria)
References: UniProt: A0R205
#2: Protein ATP synthase subunit a


Mass: 27568.482 Da / Num. of mol.: 1 / Source method: isolated from a natural source
Source: (natural) Mycolicibacterium smegmatis MC2 155 (bacteria)
References: UniProt: A0R206
#3: 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 MC2 155 (bacteria)
References: UniProt: A0R204
#4: 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 MC2 155 (bacteria)
References: UniProt: A0R203
#5: Chemical
ChemComp-YGR / (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2,3,6-trimethoxypyridin-4-yl)butan-2-ol


Mass: 657.552 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C31H37BrN4O7 / Feature type: SUBJECT OF INVESTIGATION
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: TBAJ-876-bound Mycobacterium smegmatis ATP synthase FO region
Type: COMPLEX / Entity ID: #1-#4 / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Mycolicibacterium smegmatis MC2 155 (bacteria)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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 defocus max: 2100 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 44 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 368106 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0037944
ELECTRON MICROSCOPYf_angle_d0.49410822
ELECTRON MICROSCOPYf_dihedral_angle_d13.4891176
ELECTRON MICROSCOPYf_chiral_restr0.0391248
ELECTRON MICROSCOPYf_plane_restr0.0051329

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