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- EMDB-59152: T. cruzi topoisomerase II alpha bound to dsDNA and the covalent i... -

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Basic information

Entry
Database: EMDB / ID: EMD-59152
TitleT. cruzi topoisomerase II alpha bound to dsDNA and the covalent inhibitor IID432
Map data
Sample
  • Complex: Topoisomerase II alpha bound to cleaved dsDNA and inhibitor IID432
    • Protein or peptide: DNA topoisomerase 2
    • DNA: DNA (16-Mer)
    • DNA: DNA (12-Mer)
  • Ligand: MAGNESIUM ION
  • Ligand: 2-(3-cyano-1,2,4-triazol-1-yl)-~{N}-[(3~{S})-1-(2-methylquinolin-6-yl)pyrrolidin-3-yl]ethanamide
KeywordsTopoisomerase / DNA binding protein / Topoisomerase inhibitor / ISOMERASE
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 / ATP binding / metal ion 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
Biological speciesTrypanosoma cruzi (eukaryote) / Escherichia coli (E. coli)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.77 Å
AuthorsSchenk A / Deniston C
Funding support United Kingdom, 1 items
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, 2026-
Header (metadata) releaseSep 16, 2026-
Map releaseSep 16, 2026-
UpdateSep 16, 2026-
Current statusSep 16, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_59152.png

Downloads & links

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Map

FileDownload / File: emd_59152.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 256 pix.
= 216.32 Å		0.85 Å/pix.
x 256 pix.
= 216.32 Å		0.85 Å/pix.
x 256 pix.
= 216.32 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.845 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.3
Minimum - Maximum-1.4528972 - 2.3998868
Average (Standard dev.)-0.000114841554 (±0.07909967)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 216.32 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_59152_msk_1.map
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Additional map: #1

Fileemd_59152_additional_1.map
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Half map: #2

Fileemd_59152_half_map_1.map
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Half map: #1

Fileemd_59152_half_map_2.map
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Sample components

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Entire : Topoisomerase II alpha bound to cleaved dsDNA and inhibitor IID432

EntireName: Topoisomerase II alpha bound to cleaved dsDNA and inhibitor IID432
Components
  • Complex: Topoisomerase II alpha bound to cleaved dsDNA and inhibitor IID432
    • Protein or peptide: DNA topoisomerase 2
    • DNA: DNA (16-Mer)
    • DNA: DNA (12-Mer)
  • Ligand: MAGNESIUM ION
  • Ligand: 2-(3-cyano-1,2,4-triazol-1-yl)-~{N}-[(3~{S})-1-(2-methylquinolin-6-yl)pyrrolidin-3-yl]ethanamide

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Supramolecule #1: Topoisomerase II alpha bound to cleaved dsDNA and inhibitor IID432

SupramoleculeName: Topoisomerase II alpha bound to cleaved dsDNA and inhibitor IID432
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Trypanosoma cruzi (eukaryote)

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Macromolecule #1: DNA topoisomerase 2

MacromoleculeName: DNA topoisomerase 2 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: DNA topoisomerase (ATP-hydrolysing)
Source (natural)Organism: Trypanosoma cruzi (eukaryote)
Molecular weightTheoretical: 89.322438 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GRNADRKQIL GIPKLDDANE AGGKYSHRCT LILTEGDSAK ALCTAGLAVK DRDYFGVFPL RGKPLNVRDA TLKKVMACAE FQAVSKIMG LDIRQKYSGV ERLRYGHLMI MSDQDHDGSH IKGLIINMIH HYWPDLIKTP GFLQQFITPI VKARKKGRSD G DDRAISFF ...String:
GRNADRKQIL GIPKLDDANE AGGKYSHRCT LILTEGDSAK ALCTAGLAVK DRDYFGVFPL RGKPLNVRDA TLKKVMACAE FQAVSKIMG LDIRQKYSGV ERLRYGHLMI MSDQDHDGSH IKGLIINMIH HYWPDLIKTP GFLQQFITPI VKARKKGRSD G DDRAISFF SMPDYFEWKN AIGDGIRNYE IRYYKGLGTS GAKEGREYFE NIDRHRLDFV HEDATDDARI VMAFAKDKVE ER KHWITQF KANTNVNESM NYNVRTVRYS EFVDKELILF SVADCERSIP SVIDGLKPGQ RKIIFSSFKR RLTRSIKVVQ LAG YVSEHA AYHHGEQSLV QTIVGLAQNF VGSNNVPLLQ QDGQFGTRLQ GGKDHAAGRY IFTRLTNIAR YIYHPSDDFV VDYK DDDGL SVEPFYYVPV IPMVLVNGTS GIGTGFATNI PNYSPLEVID NLMRLLRGEE VQPMKPWYFG FAGTIEEKEK GKFVS TGCA NVRPDGVVQI TELPIGTWTQ GYKKFLEELR EKEVVVQYRE HNTDVTVDFE VFLHPEVLHH WVAQGCVEER LQLREY IHA TNIIAFDREG QITKYRDAEA VLKEFYLVRL EYYAKRRDFL IGDLRSVASK LENMVRFVTE VVDGRLIVTR RRKKELL EE LRQRGYAPFP LQQKKKVSST TIQQGEEEGA ADATHATAED VFLVLQPAVD EGGDEDNQET PEMRRAARDY DYLLGMRL W NLTAEMIARL QSQLQKARDE LAALEKRTPK DLWAEDLNQL RPRIENLFEE RAKEIASI

UniProtKB: DNA topoisomerase 2

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Macromolecule #2: DNA (16-Mer)

MacromoleculeName: DNA (16-Mer) / type: dna / ID: 2 / Number of copies: 2 / Classification: DNA
Source (natural)Organism: Escherichia coli (E. coli)
Molecular weightTheoretical: 4.82414 KDa
SequenceString:
(DA)(DG)(DC)(DT)(DC)(DA)(DT)(DT)(DG)(DT) (DT)(DA)(DT)(DC)(DC)(DC)

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Macromolecule #3: DNA (12-Mer)

MacromoleculeName: DNA (12-Mer) / type: dna / ID: 3 / Number of copies: 2 / Classification: DNA
Source (natural)Organism: Escherichia coli (E. coli)
Molecular weightTheoretical: 3.735467 KDa
SequenceString:
(DG)(DG)(DG)(DA)(DT)(DA)(DA)(DC)(DA)(DA) (DT)(DG)

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Macromolecule #4: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 2 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #5: 2-(3-cyano-1,2,4-triazol-1-yl)-~{N}-[(3~{S})-1-(2-methylquinolin-...

MacromoleculeName: 2-(3-cyano-1,2,4-triazol-1-yl)-~{N}-[(3~{S})-1-(2-methylquinolin-6-yl)pyrrolidin-3-yl]ethanamide
type: ligand / ID: 5 / Number of copies: 2 / Formula: A1KFP
Molecular weightTheoretical: 361.4 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.3
Component:
ConcentrationNameFormula
20.0 mMHEPES
100.0 mMpotassium chlorideKCl
3.0 mMmagnesium chlorideMgCl2
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

DetailsUntilted and tilted data merged
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
In silico model: Initial model generated using ab-inito reconstruction in cryoSPARC
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.77 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 398902
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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