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- EMDB-37251: Structure of the human ATP synthase bound to bedaquiline (composite) -
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Basic information
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Title | Structure of the human ATP synthase bound to bedaquiline (composite) | ||||||||||||
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![]() | ATP synthase / Human / cryo-EM / Membrane protein | ||||||||||||
Function / homology | ![]() mitochondrial proton-transporting ATP synthase complex binding / regulation of ATP metabolic process / regulation of protein targeting to mitochondrion / negative regulation of cell adhesion involved in substrate-bound cell migration / Formation of ATP by chemiosmotic coupling / positive regulation of proteolysis involved in protein catabolic process / Cristae formation / positive regulation of autophagy of mitochondrion in response to mitochondrial depolarization / ATP biosynthetic process / angiostatin binding ...mitochondrial proton-transporting ATP synthase complex binding / regulation of ATP metabolic process / regulation of protein targeting to mitochondrion / negative regulation of cell adhesion involved in substrate-bound cell migration / Formation of ATP by chemiosmotic coupling / positive regulation of proteolysis involved in protein catabolic process / Cristae formation / positive regulation of autophagy of mitochondrion in response to mitochondrial depolarization / ATP biosynthetic process / angiostatin binding / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / mitochondrial depolarization / Mitochondrial protein import / ATPase inhibitor activity / negative regulation of ATP-dependent activity / mitochondrial proton-transporting ATP synthase complex assembly / negative regulation of hydrolase activity / proton-transporting ATP synthase complex / oxidative phosphorylation / cellular response to interleukin-7 / enzyme inhibitor activity / response to copper ion / response to muscle activity / cellular response to nitric oxide / heme biosynthetic process / : / : / : / : / proton-transporting ATP synthase complex, coupling factor F(o) / mitochondrial nucleoid / : / MHC class I protein binding / negative regulation of endothelial cell proliferation / proton transmembrane transporter activity / proton motive force-driven ATP synthesis / positive regulation of blood vessel endothelial cell migration / response to hyperoxia / generation of precursor metabolites and energy / proton-transporting ATP synthase complex, catalytic core F(1) / cellular response to dexamethasone stimulus / H+-transporting two-sector ATPase / substantia nigra development / proton-transporting ATPase activity, rotational mechanism / proton transmembrane transport / reactive oxygen species metabolic process / proton-transporting ATP synthase activity, rotational mechanism / erythrocyte differentiation / proton motive force-driven mitochondrial ATP synthesis / Mitochondrial protein degradation / lipid metabolic process / regulation of intracellular pH / Transcriptional activation of mitochondrial biogenesis / mitochondrial membrane / aerobic respiration / ADP binding / osteoblast differentiation / ATPase binding / nuclear membrane / protease binding / angiogenesis / response to ethanol / calmodulin binding / mitochondrial inner membrane / mitochondrial matrix / hydrolase activity / membrane raft / lipid binding / enzyme binding / cell surface / ATP hydrolysis activity / protein-containing complex / mitochondrion / RNA binding / extracellular exosome / ATP binding / identical protein binding / membrane / nucleus / plasma membrane Similarity search - Function | ||||||||||||
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Method | single particle reconstruction / cryo EM / Resolution: 2.89 Å | ||||||||||||
![]() | Lai Y / Zhang Y / Gong H | ||||||||||||
Funding support | ![]()
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![]() | ![]() Title: Inhibition of M. tuberculosis and human ATP synthase by BDQ and TBAJ-587. Authors: Yuying Zhang / Yuezheng Lai / Shan Zhou / Ting Ran / Yue Zhang / Ziqing Zhao / Ziyan Feng / Long Yu / Jinxu Xu / Kun Shi / Jianyun Wang / Yu Pang / Liang Li / Hongming Chen / Luke W Guddat / ...Authors: Yuying Zhang / Yuezheng Lai / Shan Zhou / Ting Ran / Yue Zhang / Ziqing Zhao / Ziyan Feng / Long Yu / Jinxu Xu / Kun Shi / Jianyun Wang / Yu Pang / Liang Li / Hongming Chen / Luke W Guddat / Yan Gao / Fengjiang Liu / Zihe Rao / Hongri Gong / ![]() ![]() Abstract: Bedaquiline (BDQ), a first-in-class diarylquinoline anti-tuberculosis drug, and its analogue, TBAJ-587, prevent the growth and proliferation of Mycobacterium tuberculosis by inhibiting ATP synthase. ...Bedaquiline (BDQ), a first-in-class diarylquinoline anti-tuberculosis drug, and its analogue, TBAJ-587, prevent the growth and proliferation of Mycobacterium tuberculosis by inhibiting ATP synthase. However, BDQ also inhibits human ATP synthase. At present, how these compounds interact with either M. tuberculosis ATP synthase or human ATP synthase is unclear. Here we present cryogenic electron microscopy structures of M. tuberculosis ATP synthase with and without BDQ and TBAJ-587 bound, and human ATP synthase bound to BDQ. The two inhibitors interact with subunit a and the c-ring at the leading site, c-only sites and lagging site in M. tuberculosis ATP synthase, showing that BDQ and TBAJ-587 have similar modes of action. The quinolinyl and dimethylamino units of the compounds make extensive contacts with the protein. The structure of human ATP synthase in complex with BDQ reveals that the BDQ-binding site is similar to that observed for the leading site in M. tuberculosis ATP synthase, and that the quinolinyl unit also interacts extensively with the human enzyme. This study will improve researchers' understanding of the similarities and differences between human ATP synthase and M. tuberculosis ATP synthase in terms of the mode of BDQ binding, and will allow the rational design of novel diarylquinolines as anti-tuberculosis drugs. | ||||||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 468.4 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 28.5 KB 28.5 KB | Display Display | ![]() |
Images | ![]() | 41.8 KB | ||
Filedesc metadata | ![]() | 7.9 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8ki3MC ![]() 8j0sC ![]() 8j0tC ![]() 8j57C ![]() 8j58C ![]() 8jr0C ![]() 8jr1C ![]() 8khfC C: citing same article ( M: atomic model generated by this map |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 0.73 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
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Sample components
+Entire : human ATP synthase
+Supramolecule #1: human ATP synthase
+Macromolecule #1: ATP synthase subunit alpha, mitochondrial
+Macromolecule #2: ATP synthase subunit beta, mitochondrial
+Macromolecule #3: ATP synthase subunit gamma, mitochondrial
+Macromolecule #4: ATPase inhibitor, mitochondrial
+Macromolecule #5: ATP synthase subunit O, mitochondrial
+Macromolecule #6: ATP synthase F(0) complex subunit C1, mitochondrial
+Macromolecule #7: ATP synthase subunit delta, mitochondrial
+Macromolecule #8: ATP synthase subunit epsilon, mitochondrial
+Macromolecule #9: ATP synthase F(0) complex subunit B1, mitochondrial
+Macromolecule #10: ATP synthase subunit d, mitochondrial
+Macromolecule #11: ATP synthase subunit a
+Macromolecule #12: ATP synthase subunit ATP5MJ, mitochondrial
+Macromolecule #13: ATP synthase protein 8
+Macromolecule #14: ATP synthase subunit f, mitochondrial
+Macromolecule #15: ATP synthase subunit g, mitochondrial
+Macromolecule #16: ATP synthase subunit e, mitochondrial
+Macromolecule #17: ATP synthase-coupling factor 6, mitochondrial
+Macromolecule #18: ADENOSINE-5'-TRIPHOSPHATE
+Macromolecule #19: MAGNESIUM ION
+Macromolecule #20: ADENOSINE-5'-DIPHOSPHATE
+Macromolecule #21: Bedaquiline
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.2 µm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Startup model | Type of model: PDB ENTRY PDB model - PDB ID: |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.89 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 84037 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |