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- PDB-8s7k: M. tuberculosis gyrase holocomplex with 150 bp DNA and gepotidacin -

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Basic information

Entry
Database: PDB / ID: 8s7k
TitleM. tuberculosis gyrase holocomplex with 150 bp DNA and gepotidacin
Components
  • (DNA (5'-D(*AP*GP*TP*AP*TP*TP*AP*CP*CP*CP*CP*TP*TP*CP*CP*GP*GP*A)- ...) x 2
  • (DNA gyrase subunit ...) x 2
KeywordsDNA BINDING PROTEIN / Mycobacterium tuberculosis / DNA gyrase / Novel Bacterial Topoisomerase II Inhibitors / antibiotic resistance / structure-activity relation
Function / homology
Function and homology information


DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) complex / DNA negative supercoiling activity / DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) activity / DNA topoisomerase (ATP-hydrolysing) / DNA topological change / peptidoglycan-based cell wall / DNA-templated DNA replication / chromosome / response to antibiotic / magnesium ion binding ...DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) complex / DNA negative supercoiling activity / DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) activity / DNA topoisomerase (ATP-hydrolysing) / DNA topological change / peptidoglycan-based cell wall / DNA-templated DNA replication / chromosome / response to antibiotic / magnesium ion binding / ATP hydrolysis activity / DNA binding / ATP binding / plasma membrane / cytoplasm
Similarity search - Function
DNA gyrase, subunit A / DNA gyrase/topoisomerase IV, subunit A, C-terminal repeat / DNA gyrase/topoisomerase IV, subunit A, C-terminal / : / DNA gyrase C-terminal domain, beta-propeller / DNA gyrase subunit B, TOPRIM domain / DNA gyrase, subunit B / DNA topoisomerase, type IIA, subunit B / DNA gyrase B subunit, C-terminal / DNA gyrase B subunit, carboxyl terminus ...DNA gyrase, subunit A / DNA gyrase/topoisomerase IV, subunit A, C-terminal repeat / DNA gyrase/topoisomerase IV, subunit A, C-terminal / : / DNA gyrase C-terminal domain, beta-propeller / DNA gyrase subunit B, TOPRIM domain / DNA gyrase, subunit B / DNA topoisomerase, type IIA, subunit B / DNA gyrase B subunit, C-terminal / DNA gyrase B subunit, carboxyl terminus / Topoisomerase (Topo) IIA-type catalytic domain profile. / DNA topoisomerase, type IIA, alpha-helical domain superfamily / DNA topoisomerase, type IIA, domain A / DNA topoisomerase, type IIA, domain A, alpha-beta / DNA gyrase/topoisomerase IV, subunit A / DNA Topoisomerase IV / DNA topoisomerase, type IIA, subunit B, domain 2 / DNA gyrase B / DNA topoisomerase, type IIA / DNA topoisomerase, type IIA, conserved site / DNA topoisomerase II signature. / TopoisomeraseII / DNA topoisomerase, type IIA, subunit B, C-terminal / Toprim domain / DNA topoisomerase, type IIA-like domain superfamily / Toprim domain profile. / TOPRIM domain / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase / Histidine kinase/HSP90-like ATPase superfamily / EF-hand calcium-binding domain. / Ribosomal protein S5 domain 2-type fold, subgroup / Ribosomal protein S5 domain 2-type fold
Similarity search - Domain/homology
Chem-JHN / DNA / DNA (> 10) / DNA (> 100) / DNA gyrase subunit B / DNA gyrase subunit A
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsMechaly, A. / Gubellini, F. / Yab, E. / Willand, N. / Petrella, S.
Funding support France, 3items
OrganizationGrant numberCountry
IdEx Universite Paris Cite France
Agence Nationale de la Recherche (ANR)ANR-18-IDEX-0001 France
Fondation pour la Recherche Medicale (FRM)EQU202303016284 France
CitationJournal: iScience / Year: 2024
Title: Molecular mechanism of a triazole-containing inhibitor of DNA gyrase.
Authors: Antoine Gedeon / Emilie Yab / Aurelia Dinut / Elodie Sadowski / Estelle Capton / Aurore Dreneau / Julienne Petit / Bruna Gioia / Catherine Piveteau / Kamel Djaout / Estelle Lecat / Anne ...Authors: Antoine Gedeon / Emilie Yab / Aurelia Dinut / Elodie Sadowski / Estelle Capton / Aurore Dreneau / Julienne Petit / Bruna Gioia / Catherine Piveteau / Kamel Djaout / Estelle Lecat / Anne Marie Wehenkel / Francesca Gubellini / Ariel Mechaly / Pedro M Alzari / Benoît Deprez / Alain Baulard / Alexandra Aubry / Nicolas Willand / Stéphanie Petrella /
Abstract: Antimicrobial resistance remains a persistent and pressing public health concern. Here, we describe the synthesis of original triazole-containing inhibitors targeting the DNA gyrase, a well-validated ...Antimicrobial resistance remains a persistent and pressing public health concern. Here, we describe the synthesis of original triazole-containing inhibitors targeting the DNA gyrase, a well-validated drug target for developing new antibiotics. Our compounds demonstrate potent antibacterial activity against various pathogenic bacteria, with notable potency against (). Moreover, one hit, compound , named BDM71403, was shown to be more potent in than the NBTI of reference, gepotidacin. Mechanistic enzymology assays reveal a competitive interaction of BDM71403 with fluoroquinolones within the gyrase cleavage core. High-resolution cryo-electron microscopy structural analysis provides detailed insights into the ternary complex formed by the gyrase, double-stranded DNA, and either BDM71403 or gepotidacin, providing a rational framework to understand the superior efficacy on . This study highlights the potential of triazole-based scaffolds as promising gyrase inhibitors, offering new avenues for drug development in the fight against antimicrobial resistance.
History
DepositionMar 1, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 8, 2025Provider: repository / Type: Initial release
Revision 1.0Oct 8, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Oct 8, 2025Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Oct 8, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Oct 8, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Oct 8, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
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Revision 1.1May 13, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.1May 13, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: DNA gyrase subunit A
A: DNA gyrase subunit A
B: DNA gyrase subunit B
D: DNA gyrase subunit B
E: DNA (5'-D(*AP*GP*TP*AP*TP*TP*AP*CP*CP*CP*CP*TP*TP*CP*CP*GP*GP*A)-3')
F: DNA (5'-D(*AP*GP*TP*AP*TP*TP*AP*CP*CP*CP*CP*TP*TP*CP*CP*GP*GP*A)-3')
hetero molecules


Theoretical massNumber of molelcules
Total (without water)426,5709
Polymers426,0736
Non-polymers4973
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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DNA gyrase subunit ... , 2 types, 4 molecules CABD

#1: Protein DNA gyrase subunit A / Type IIA topoisomerase subunit GyrA


Mass: 92304.180 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (bacteria) / Gene: gyrA, Rv0006, MTCY10H4.04 / Production host: Escherichia coli (E. coli)
References: UniProt: P9WG47, DNA topoisomerase (ATP-hydrolysing)
#2: Protein DNA gyrase subunit B


Mass: 74423.953 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (bacteria) / Gene: gyrB, Rv0005, MTCY10H4.03 / Production host: Escherichia coli (E. coli)
References: UniProt: P9WG45, DNA topoisomerase (ATP-hydrolysing)

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DNA (5'-D(*AP*GP*TP*AP*TP*TP*AP*CP*CP*CP*CP*TP*TP*CP*CP*GP*GP*A)- ... , 2 types, 2 molecules EF

#3: DNA chain DNA (5'-D(*AP*GP*TP*AP*TP*TP*AP*CP*CP*CP*CP*TP*TP*CP*CP*GP*GP*A)-3')


Mass: 46325.371 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#4: DNA chain DNA (5'-D(*AP*GP*TP*AP*TP*TP*AP*CP*CP*CP*CP*TP*TP*CP*CP*GP*GP*A)-3')


Mass: 46291.480 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 2 types, 3 molecules

#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#6: Chemical ChemComp-JHN / (3~{R})-3-[[4-(3,4-dihydro-2~{H}-pyrano[2,3-c]pyridin-6-ylmethylamino)piperidin-1-yl]methyl]-1,4,7-triazatricyclo[6.3.1.0^{4,12}]dodeca-6,8(12),9-triene-5,11-dione


Mass: 448.518 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H28N6O3 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationN

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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

Component
IDNameTypeEntity IDParent-IDSource
1Cryo-EM structure of Mtb DNA Gyrase in complex with DNA and GepotidacinCOMPLEX#1-#40MULTIPLE SOURCES
2DNA gyraseCOMPLEX#1-#21RECOMBINANT
3DNACOMPLEX#3-#41RECOMBINANT
Molecular weightValue: 0.43 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Mycobacterium tuberculosis (bacteria)1773
33synthetic construct (others)32630
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Escherichia coli (E. coli)562
33synthetic construct (others)32630
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE / Humidity: 100 %

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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: DIFFRACTION / Nominal defocus max: 2800 nm / Nominal defocus min: 800 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 830271 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00211572
ELECTRON MICROSCOPYf_angle_d0.48715811
ELECTRON MICROSCOPYf_dihedral_angle_d13.1661908
ELECTRON MICROSCOPYf_chiral_restr0.0391790
ELECTRON MICROSCOPYf_plane_restr0.0031952

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