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- PDB-36ap: Mycobacterium tuberculosis DNA Gyrase catalytic core in complex w... -

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Basic information

Entry
Database: PDB / ID: 36ap
TitleMycobacterium tuberculosis DNA Gyrase catalytic core in complex with DNA and indole-3-acetyl-L-aspartic acid
Components
  • (DNA gyrase subunit ...) x 2
  • DNA (5'-D(P*AP*AP*TP*GP*CP*AP*CP*GP*TP*AP*T)-3')
  • DNA (5'-D(P*AP*TP*AP*CP*GP*TP*GP*CP*AP*T)-3')
  • DNA (5'-D(P*GP*GP*TP*CP*AP*TP*GP*AP*A)-3')
  • DNA (5'-D(P*TP*TP*CP*AP*TP*GP*AP*C)-3')
KeywordsOXIDOREDUCTASE / Mycobacterium tuberculosis / InhA / Inhibitory adduct / Resistance / Mutation
Function / homology
Function and homology information


DNA negative supercoiling activity / DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) complex / DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) activity / DNA topoisomerase (ATP-hydrolysing) / DNA topological change / DNA-templated DNA replication / chromosome / magnesium ion binding / ATP hydrolysis activity / DNA binding ...DNA negative supercoiling activity / DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) complex / DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) activity / DNA topoisomerase (ATP-hydrolysing) / DNA topological change / DNA-templated DNA replication / chromosome / 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
N-[1H-INDOL-3-YL-ACETYL]ASPARTIC ACID / DNA / DNA (> 10) / 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: 2.64 Å
AuthorsRossini, N.O. / Dias, M.V.B. / Coureux, P.D.
Funding support Brazil, 2items
OrganizationGrant numberCountry
Sao Paulo Research Foundation (FAPESP) Brazil
Brazilian National Council for Scientific and Technological Development (CNPq) Brazil
CitationJournal: Eur J Med Chem / Year: 2026
Title: Fragment-based drug discovery strategy reveals an unprecedented allosteric binding site in Mycobacterium tuberculosis DNA gyrase.
Authors: Sabrina T Shiroma / Nicolas O Rossini / Jillian F Armenia / Catharina S Silva / Paulo C T Souza / Pierre-Damien Coureux / Neil Osheroff / Marcio V B Dias /
Abstract: Tuberculosis remains a serious public health threat and the leading infectious cause of death worldwide. Tuberculosis treatment requires at least four antimicrobial drugs and is associated with ...Tuberculosis remains a serious public health threat and the leading infectious cause of death worldwide. Tuberculosis treatment requires at least four antimicrobial drugs and is associated with adverse effects and prolonged therapy, compromising adherence and increasing the risk of drug resistance. Therefore, developing new antitubercular therapies remains essential. Mycobacterium tuberculosis, the primary etiological agent of tuberculosis, lacks topoisomerase IV, making DNA gyrase its sole type II topoisomerase and an attractive drug target. Although fluoroquinolones such as moxifloxacin are used to treat tuberculosis, resistance has limited their effectiveness. Here, we applied a fragment-based drug discovery approach to identify and validate low-affinity compounds targeting M. tuberculosis DNA gyrase as starting points for inhibitor development. Using complementary biophysical and biochemical techniques, we identified five compounds that bind DNA gyrase and inhibit DNA supercoiling and DNA cleavage activities. These compounds interfere with early steps of the gyrase catalytic cycle, likely by blocking conformational changes required for DNA cleavage. The cryo-electron microscopy structure of DNA gyrase in complex with the most potent compound revealed binding near the GyrA-GyrB interface and extensive conformational changes in the GyrB TOPRIM domain. These findings provide a foundation for developing antitubercular agents with a novel mechanism of action.
History
DepositionMay 28, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 28, 2026Provider: repository / Type: Initial release
Revision 1.0Oct 28, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: DNA gyrase subunit A
B: DNA gyrase subunit B
C: DNA gyrase subunit A
D: DNA gyrase subunit B
E: DNA (5'-D(P*AP*AP*TP*GP*CP*AP*CP*GP*TP*AP*T)-3')
H: DNA (5'-D(P*AP*TP*AP*CP*GP*TP*GP*CP*AP*T)-3')
F: DNA (5'-D(P*TP*TP*CP*AP*TP*GP*AP*C)-3')
G: DNA (5'-D(P*GP*GP*TP*CP*AP*TP*GP*AP*A)-3')
hetero molecules


Theoretical massNumber of molelcules
Total (without water)181,02014
Polymers179,8108
Non-polymers1,2106
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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DNA gyrase subunit ... , 2 types, 4 molecules ACBD

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


Mass: 55928.262 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: 28185.334 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 chain , 4 types, 4 molecules EHFG

#3: DNA chain DNA (5'-D(P*AP*AP*TP*GP*CP*AP*CP*GP*TP*AP*T)-3')


Mass: 3357.223 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#4: DNA chain DNA (5'-D(P*AP*TP*AP*CP*GP*TP*GP*CP*AP*T)-3')


Mass: 3044.017 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#5: DNA chain DNA (5'-D(P*TP*TP*CP*AP*TP*GP*AP*C)-3')


Mass: 2401.604 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#6: DNA chain DNA (5'-D(P*GP*GP*TP*CP*AP*TP*GP*AP*A)-3')


Mass: 2779.848 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 2 types, 6 molecules

#7: Chemical
ChemComp-IAD / N-[1H-INDOL-3-YL-ACETYL]ASPARTIC ACID


Mass: 290.271 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H14N2O5 / Feature type: SUBJECT OF INVESTIGATION
#8: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg

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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

ComponentName: Tetrameric structure of APO InhA mutant I95P / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.114 MDa / Experimental value: YES
Source (natural)Organism: Mycobacterium tuberculosis (bacteria)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMSodium chlorideNaCl1
220 mMHepesC8H18N2O4S1
SpecimenConc.: 0.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 298 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 52 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)
EM imaging opticsEnergyfilter name: GIF Quantum LS

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.21.2_5419model refinement
5cryoSPARCCTF correction
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 13185442
3D reconstructionResolution: 2.64 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 61358 / Symmetry type: POINT
RefinementHighest resolution: 2.64 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00312673
ELECTRON MICROSCOPYf_angle_d0.73817280
ELECTRON MICROSCOPYf_dihedral_angle_d16.152106
ELECTRON MICROSCOPYf_chiral_restr0.0421947
ELECTRON MICROSCOPYf_plane_restr0.0062147

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