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TitleMechanism of mycobacterial ATP synthase inhibition by squaramides and second generation diarylquinolines.
Journal, issue, pagesEMBO J, Vol. 42, Issue 15, Page e113687, Year 2023
Publish dateAug 1, 2023
AuthorsGautier M Courbon / Paul R Palme / Lea Mann / Adrian Richter / Peter Imming / John L Rubinstein /
PubMed AbstractMycobacteria, 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.
External linksEMBO J / PubMed:37377118 / PubMed Central
MethodsEM (single particle)
Resolution2.6 - 3.1 Å
Structure data

EMDB-29648, PDB-8g07:
Cryo-EM structure of SQ31f-bound Mycobacterium smegmatis ATP synthase FO region
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-29649: Cryo-EM structure of SQ31f-bound Mycobacterium smegmatis ATP synthase rotational state 1
PDB-8g08: Cryo-EM structure of SQ31f-bound Mycobacterium smegmatis ATP synthase rotational state 1 (backbone model)
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-29650: Cryo-EM structure of SQ31f-bound Mycobacterium smegmatis ATP synthase rotational state 2
PDB-8g09: Cryo-EM structure of SQ31f-bound Mycobacterium smegmatis ATP synthase rotational state 2 (backbone model)
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-29651, PDB-8g0a:
Cryo-EM structure of SQ31f-bound Mycobacterium smegmatis ATP synthase rotational state 3
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-29652, PDB-8g0b:
Cryo-EM structure of TBAJ-876-bound Mycobacterium smegmatis ATP synthase FO region
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-29653: Cryo-EM structure of TBAJ-876-bound Mycobacterium smegmatis ATP synthase rotational state 1
PDB-8g0c: Cryo-EM structure of TBAJ-876-bound Mycobacterium smegmatis ATP synthase rotational state 1 (backbone model)
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-29654: Cryo-EM structure of TBAJ-876-bound Mycobacterium smegmatis ATP synthase rotational state 2
PDB-8g0d: Cryo-EM structure of TBAJ-876-bound Mycobacterium smegmatis ATP synthase rotational state 2 (backbone model)
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-29655, PDB-8g0e:
Cryo-EM structure of TBAJ-876-bound Mycobacterium smegmatis ATP synthase rotational state 3
Method: EM (single particle) / Resolution: 2.6 Å

Chemicals

ChemComp-SQC:
3-[4-(morpholin-4-yl)phenyl]-4-{[(pyridin-2-yl)methyl]amino}cyclobut-3-ene-1,2-dione

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-MG:
Unknown entry

ChemComp-PO4:
PHOSPHATE ION

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

Source
  • mycolicibacterium smegmatis mc2 155 (bacteria)
KeywordsTRANSLOCASE/INHIBITOR / ATP synthase / mycobacterial / inhibitor / tuberculosis / antibiotic / HYDROLASE / TRANSLOCASE-INHIBITOR complex

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