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- PDB-32to: T. cruzi topoisomerase II alpha bound to dsDNA and the covalent i... -

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Basic information

Entry
Database: PDB / ID: 32to
TitleT. cruzi topoisomerase II alpha bound to dsDNA and the covalent inhibitor IID432
Components
  • DNA (12-Mer)
  • DNA (16-Mer)
  • DNA topoisomerase 2
KeywordsISOMERASE / Topoisomerase / DNA binding protein / Topoisomerase inhibitor
Function / homology
Function and homology information


sister chromatid segregation / resolution of meiotic recombination intermediates / DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) activity / DNA topoisomerase (ATP-hydrolysing) / DNA topological change / DNA binding / metal ion binding / ATP binding / nucleus
Similarity search - Function
DNA topoisomerase 2, TOPRIM domain / C-terminal associated domain of TOPRIM / C-terminal associated domain of TOPRIM / DNA topoisomerase II, eukaryotic-type / : / 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 2, TOPRIM domain / C-terminal associated domain of TOPRIM / C-terminal associated domain of TOPRIM / DNA topoisomerase II, eukaryotic-type / : / 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 / DNA topoisomerase, type IIA-like domain superfamily / Toprim domain profile. / TOPRIM domain / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase/HSP90-like ATPase / Histidine kinase/HSP90-like ATPase superfamily / Ribosomal protein S5 domain 2-type fold, subgroup / Ribosomal protein S5 domain 2-type fold
Similarity search - Domain/homology
: / DNA / DNA (> 10) / DNA topoisomerase 2
Similarity search - Component
Biological speciesTrypanosoma cruzi (eukaryote)
Escherichia coli (E. coli)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.77 Å
AuthorsSchenk, A. / Deniston, C.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome Trust219639/Z/19/Z United Kingdom
CitationJournal: Proc Natl Acad Sci U S A / Year: 2026
Title: IID432, a parasite-selective topoisomerase II inhibitor, achieves rapid single-dose parasite clearance in a murine chronic Chagas model.
Authors: Manuel Saldivia / Rajiv S Jumani / Bryanna Thomas / Grace M Baxley / Jayant Sancheti / Domenico Bullara / Jean-Rene Galarneau / Harry Cheung / Yen-Liang Chen / Reginara Souza DeAsis / ...Authors: Manuel Saldivia / Rajiv S Jumani / Bryanna Thomas / Grace M Baxley / Jayant Sancheti / Domenico Bullara / Jean-Rene Galarneau / Harry Cheung / Yen-Liang Chen / Reginara Souza DeAsis / Debjani Patra / Olivier René / Jonas Noeske / Andreas D Schenk / Colin Deniston / Samarth Thakore / Catherine Luu / Charles Wartchow / Dennis C Koester / Amanda Fortes Francisco / Johanne Blais / Jan Jiricek / Scott A Hollingsworth / Jonathan E Gable / John M Kelly / Natasha Hochberg / Charlie G Knutson / Suresh B Lakshminarayana / Christopher Sarko / Ujjini H Manjunatha / Colin S Osborne / Thierry T Diagana / Srinivasa P S Rao /
Abstract: Chagas disease is a neglected disease that affects millions of people from the Latin American region. Current nitroheterocyclic therapies suffer from long treatment duration and safety-related ...Chagas disease is a neglected disease that affects millions of people from the Latin American region. Current nitroheterocyclic therapies suffer from long treatment duration and safety-related treatment discontinuations. A safe, short course therapy would significantly benefit Chagas patients. Here, we report the comprehensive biological, structural, pharmacodynamic, and pharmacokinetic characterization of IID432, an optimized cyanotriazole with superior potency, favorable pharmacokinetics, and improved safety profile compared to the lead compound CT1. IID432 is a fast-acting, parasite-selective topoisomerase II poison that achieves sterile cure after a single oral dose in a murine model of chronic Trypanosoma cruzi infection. Mechanistically, IID432 stabilizes the parasite TcTopoII-DNA cleavage complex by covalently engaging a parasite-specific cysteine (Cys477), thereby conferring selectivity over the human TOP2A. IID432 displays favorable oral pharmacokinetics, with no off-target activity on human topoisomerases. Brief exposure of IID432 rapidly induces parasite-specific DNA damage and produces sterilizing activity in vitro and in vivo without recrudescence. Together, these findings identify IID432 as a first-in-class, parasite-selective covalent topoisomerase poison with a potential to significantly shorten treatment duration for infections.
History
DepositionJul 24, 2026Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 16, 2026Provider: repository / Type: Initial release
Revision 1.0Sep 16, 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

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Assembly

Deposited unit
A: DNA topoisomerase 2
B: DNA topoisomerase 2
C: DNA (16-Mer)
D: DNA (12-Mer)
I: DNA (12-Mer)
J: DNA (16-Mer)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)196,53610
Polymers195,7646
Non-polymers7714
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

#1: Protein DNA topoisomerase 2


Mass: 89322.438 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Trypanosoma cruzi (eukaryote) / Gene: Tc00.1047053508699.10 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q4DE53, DNA topoisomerase (ATP-hydrolysing)
#2: DNA chain DNA (16-Mer)


Mass: 4824.140 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Escherichia coli (E. coli)
#3: DNA chain DNA (12-Mer)


Mass: 3735.467 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Escherichia coli (E. coli)
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-A1KFP / 2-(3-cyano-1,2,4-triazol-1-yl)-~{N}-[(3~{S})-1-(2-methylquinolin-6-yl)pyrrolidin-3-yl]ethanamide / LIPID FRAGMENT


Mass: 361.400 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H19N7O / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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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: Topoisomerase II alpha bound to cleaved dsDNA and inhibitor IID432
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Source (natural)Organism: Trypanosoma cruzi (eukaryote)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.3
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPES1
2100 mMpotassium chlorideKCl1
33 mMmagnesium chlorideMgCl21
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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
9PHENIX1.20.1_4487model refinement
13cryoSPARC3D reconstruction
Image processingDetails: Untilted and tilted data merged
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.77 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 398902 / Symmetry type: POINT
RefinementHighest resolution: 2.77 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00211742
ELECTRON MICROSCOPYf_angle_d0.50216168
ELECTRON MICROSCOPYf_dihedral_angle_d16.5522102
ELECTRON MICROSCOPYf_chiral_restr0.0371848
ELECTRON MICROSCOPYf_plane_restr0.0031934

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