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- PDB-8khf: Structure of the human ATP synthase bound to bedaquiline (membran... -

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Basic information

Entry
Database: PDB / ID: 8khf
TitleStructure of the human ATP synthase bound to bedaquiline (membrane domain)
Components
  • (ATP synthase F(0) complex subunit ...) x 2
  • (ATP synthase subunit ...) x 9
  • ATP synthase protein 8
KeywordsMEMBRANE PROTEIN / ATP synthase / Human / cryo-EM
Function / homology
Function and homology information


Formation of ATP by chemiosmotic coupling / Cristae formation / ATP biosynthetic process / mitochondrial proton-transporting ATP synthase complex assembly / Mitochondrial protein import / response to copper ion / proton channel activity / oxidative phosphorylation / proton-transporting ATP synthase complex / proton transmembrane transporter activity ...Formation of ATP by chemiosmotic coupling / Cristae formation / ATP biosynthetic process / mitochondrial proton-transporting ATP synthase complex assembly / Mitochondrial protein import / response to copper ion / proton channel activity / oxidative phosphorylation / proton-transporting ATP synthase complex / proton transmembrane transporter activity / proton motive force-driven ATP synthesis / proton motive force-driven mitochondrial ATP synthesis / : / : / response to hyperoxia / substantia nigra development / Mitochondrial protein degradation / proton-transporting ATP synthase activity, rotational mechanism / proton transmembrane transport / aerobic respiration / fibrillar center / nuclear membrane / mitochondrial inner membrane / hydrolase activity / mitochondrial matrix / lipid binding / structural molecule activity / mitochondrion / RNA binding / nucleus / membrane
Similarity search - Function
ATP synthase subunit ATP5MJ, mitochondrial / Mitochondrial proteolipid / ATP synthase, F0 complex, subunit G, mitochondrial / ATP synthase, F0 complex, subunit E, mitochondrial / Mitochondrial ATP synthase subunit g, animal / Mitochondrial ATP synthase g subunit / ATP synthase E chain / ATP synthase protein 8, metazoa / Mitochondrial F1-F0 ATP synthase subunit F, predicted / ATP synthase protein 8, mammals ...ATP synthase subunit ATP5MJ, mitochondrial / Mitochondrial proteolipid / ATP synthase, F0 complex, subunit G, mitochondrial / ATP synthase, F0 complex, subunit E, mitochondrial / Mitochondrial ATP synthase subunit g, animal / Mitochondrial ATP synthase g subunit / ATP synthase E chain / ATP synthase protein 8, metazoa / Mitochondrial F1-F0 ATP synthase subunit F, predicted / ATP synthase protein 8, mammals / ATP synthase protein 8 / Mitochondrial F1F0-ATP synthase, subunit f / : / Metazoan delta subunit of F1F0-ATP synthase, C-terminal domain / ATP synthase delta/epsilon subunit, C-terminal domain superfamily / ATP synthase, F0 complex, subunit B/MI25 / ATP synthase, F0 complex, subunit B / Mitochondrial ATP synthase B chain precursor (ATP-synt_B) / ATP synthase, F0 complex, subunit D, mitochondrial / ATP synthase D chain, mitochondrial (ATP5H) / ATP synthase, F0 complex, subunit D superfamily, mitochondrial / ATP synthase, F0 complex, subunit A, bacterial/mitochondria / ATP synthase, F1 complex, epsilon subunit, mitochondrial / ATP synthase, F1 complex, epsilon subunit superfamily, mitochondrial / Mitochondrial ATP synthase epsilon chain / 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. / 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, gamma subunit / ATP synthase, F1 complex, gamma subunit superfamily / ATP synthase / V-ATPase proteolipid subunit C-like domain / F/V-ATP synthase subunit C superfamily / ATP synthase subunit C
Similarity search - Domain/homology
Bedaquiline / ATP synthase peripheral stalk subunit d, mitochondrial / ATP synthase F(0) complex subunit g, mitochondrial / ATP synthase F(0) complex subunit a / ATP synthase F(0) complex subunit 8 / ATP synthase F(0) complex subunit C1, mitochondrial / ATP synthase peripheral stalk subunit b, mitochondrial / ATP synthase F(1) complex subunit delta, mitochondrial / ATP synthase F(1) complex subunit gamma, mitochondrial / ATP synthase F(0) complex subunit f, mitochondrial ...Bedaquiline / ATP synthase peripheral stalk subunit d, mitochondrial / ATP synthase F(0) complex subunit g, mitochondrial / ATP synthase F(0) complex subunit a / ATP synthase F(0) complex subunit 8 / ATP synthase F(0) complex subunit C1, mitochondrial / ATP synthase peripheral stalk subunit b, mitochondrial / ATP synthase F(1) complex subunit delta, mitochondrial / ATP synthase F(1) complex subunit gamma, mitochondrial / ATP synthase F(0) complex subunit f, mitochondrial / ATP synthase F(0) complex subunit j, mitochondrial / ATP synthase F(1) complex subunit epsilon, mitochondrial / ATP synthase F(0) complex subunit e, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.13 Å
AuthorsLai, Y. / Zhang, Y.
Funding support China, 3items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81520108019 China
National Natural Science Foundation of China (NSFC)32100976 China
National Natural Science Foundation of China (NSFC)82222042 China
CitationJournal: Nature / Year: 2024
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
DepositionAug 21, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 1, 2024Provider: repository / Type: Initial release
Revision 1.1Aug 21, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
1: ATP synthase F(0) complex subunit C1, mitochondrial
2: ATP synthase F(0) complex subunit C1, mitochondrial
3: ATP synthase F(0) complex subunit C1, mitochondrial
4: ATP synthase F(0) complex subunit C1, mitochondrial
5: ATP synthase F(0) complex subunit C1, mitochondrial
6: ATP synthase F(0) complex subunit C1, mitochondrial
7: ATP synthase F(0) complex subunit C1, mitochondrial
8: ATP synthase F(0) complex subunit C1, mitochondrial
G: ATP synthase subunit gamma, mitochondrial
H: ATP synthase subunit delta, mitochondrial
I: ATP synthase subunit epsilon, mitochondrial
K: ATP synthase F(0) complex subunit B1, mitochondrial
M: ATP synthase subunit d, mitochondrial
N: ATP synthase subunit a
P: ATP synthase subunit ATP5MJ, mitochondrial
Q: ATP synthase protein 8
R: ATP synthase subunit f, mitochondrial
S: ATP synthase subunit g, mitochondrial
T: ATP synthase subunit e, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)225,08220
Polymers224,52619
Non-polymers5561
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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ATP synthase F(0) complex subunit ... , 2 types, 9 molecules 12345678K

#1: Protein
ATP synthase F(0) complex subunit C1, mitochondrial / ATP synthase lipid-binding protein / ATP synthase membrane subunit c locus 1 / ATP synthase ...ATP synthase lipid-binding protein / ATP synthase membrane subunit c locus 1 / ATP synthase proteolipid P1 / ATP synthase proton-transporting mitochondrial F(0) complex subunit C1 / ATPase protein 9 / ATPase subunit c


Mass: 7610.954 Da / Num. of mol.: 8 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P05496
#5: Protein ATP synthase F(0) complex subunit B1, mitochondrial / ATP synthase peripheral stalk-membrane subunit b / ATP synthase proton-transporting mitochondrial ...ATP synthase peripheral stalk-membrane subunit b / ATP synthase proton-transporting mitochondrial F(0) complex subunit B1 / ATP synthase subunit b / ATPase subunit b


Mass: 24658.586 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P24539

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ATP synthase subunit ... , 9 types, 9 molecules GHIMNPRST

#2: Protein ATP synthase subunit gamma, mitochondrial / ATP synthase F1 subunit gamma / F-ATPase gamma subunit


Mass: 30207.752 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P36542
#3: Protein ATP synthase subunit delta, mitochondrial / ATP synthase F1 subunit delta / F-ATPase delta subunit


Mass: 15029.817 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P30049
#4: Protein ATP synthase subunit epsilon, mitochondrial / ATPase subunit epsilon / ATP synthase F1 subunit epsilon


Mass: 5790.779 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P56381
#6: Protein ATP synthase subunit d, mitochondrial / ATPase subunit d / ATP synthase peripheral stalk subunit d


Mass: 18383.982 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: O75947
#7: Protein ATP synthase subunit a / F-ATPase protein 6


Mass: 24833.102 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00846
#8: Protein ATP synthase subunit ATP5MJ, mitochondrial / 6.8 kDa mitochondrial proteolipid protein / MLQ / ATP synthase membrane subunit 6.8PL


Mass: 6673.053 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P56378
#10: Protein ATP synthase subunit f, mitochondrial / ATP synthase membrane subunit f


Mass: 10804.686 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P56134
#11: Protein ATP synthase subunit g, mitochondrial / ATPase subunit g / ATP synthase membrane subunit g


Mass: 11309.226 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: O75964
#12: Protein ATP synthase subunit e, mitochondrial / ATPase subunit e / ATP synthase membrane subunit e


Mass: 7947.215 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P56385

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Protein / Non-polymers , 2 types, 2 molecules Q

#13: Chemical ChemComp-BQ1 / Bedaquiline


Mass: 555.505 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H31BrN2O2 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, antibiotic*YM
#9: Protein ATP synthase protein 8 / A6L / F-ATPase subunit 8


Mass: 8000.634 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P03928

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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: human ATP synthase / Type: COMPLEX / Entity ID: #1-#12 / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
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: 2400 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.13 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 84037 / Symmetry type: POINT

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