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- EMDB-58649: DNA-bound POLQTaqChimera in complex with compound 41 -

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Basic information

Entry
Database: EMDB / ID: EMD-58649
TitleDNA-bound POLQTaqChimera in complex with compound 41
Map data
Sample
  • Complex: Chimera of PolQ and Taq polymerase bound to DNA and compound 41.
    • Protein or peptide: PolQTaq chimera
KeywordsPolymerase / REPLICATION
Biological speciessynthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsShilliday F / Maia de Oliveira T
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: J Med Chem / Year: 2026
Title: Discovery of a Novel Series of Benzimidazoles/Purines as Potent, Selective and Orally Active Inhibitors of the DNA Polymerase Activity of POLQ.
Authors: Bernard Barlaam / Nina Akrap / Derek Barratt / Michael S Bodnarchuk / Elaine B Cadogan / Sarah Jane Caswell / Kimberly Cook / Josep V Forment / Ariamala Gopalsamy / Daniel Griffiths / Craig ...Authors: Bernard Barlaam / Nina Akrap / Derek Barratt / Michael S Bodnarchuk / Elaine B Cadogan / Sarah Jane Caswell / Kimberly Cook / Josep V Forment / Ariamala Gopalsamy / Daniel Griffiths / Craig Hughes / Pamela A Lochhead / David Longmire / Taiana Maia de Oliveira / Marcello Maresca / Jennifer I Moss / Bo Peng / Alexander Pflug / Andy Pike / Christelle de Renty / Jason D Shields / Fiona Shilliday / Harriet Southgate / Christopher J Stubbs / Sandeep K Talapatra / Oliver Turner / Paul Turner / Elizabeth Underwood / Christina Vasalou / Jamie Ware / Poppy Winlow / Jon J Winter-Holt / Gail Wrigley / Lin Xue / Jingrui Zhang / Ke Zhang /
Abstract: DNA polymerase θ (Polθ, gene POLQ) is a key enzyme in the microhomology-mediated end joining (MMEJ) pathway to repair DNA double strand breaks (DSB). Here we report the discovery of novel, potent, ...DNA polymerase θ (Polθ, gene POLQ) is a key enzyme in the microhomology-mediated end joining (MMEJ) pathway to repair DNA double strand breaks (DSB). Here we report the discovery of novel, potent, selective and orally active inhibitors of the DNA polymerase activity of POLQ. Starting from a weak inhibitor of POLQ (compound 1, IC50 0.8 μM, biochemical assay), further optimization of the series led to compound 37, a potent inhibitor of POLQ (IC50 < 0.003 μM, biochemical assay), which suppressed the cellular MMEJ pathway activity (IC50 0.10 μM), showed anti-proliferative activity in homologous recombination repair (HRR) deficient cell lines (e.g. BRCA2-/- DLD-1 IC50 0.058 μM), and enhanced antiproliferative activity of the PARP 1/2 inhibitor olaparib in multiple HRR defective cell lines, with no activity in HRR proficient settings. Compound 37 showed tumor regression in the BRCA2-/- DLD-1 murine xenograft model after chronic oral dosing in combination with olaparib.
History
DepositionJun 22, 2026-
Header (metadata) releaseNov 4, 2026-
Map releaseNov 4, 2026-
UpdateNov 4, 2026-
Current statusNov 4, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_58649.png

Downloads & links

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Map

FileDownload / File: emd_58649.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.65 Å/pix.
x 300 pix.
= 195. Å		0.65 Å/pix.
x 300 pix.
= 195. Å		0.65 Å/pix.
x 300 pix.
= 195. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.65 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.045
Minimum - Maximum-0.14716992 - 0.23775578
Average (Standard dev.)0.00007904969 (±0.0062125023)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 195.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_58649_msk_1.map
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Half map: #2

Fileemd_58649_half_map_1.map
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Half map: #1

Fileemd_58649_half_map_2.map
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Sample components

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Entire : Chimera of PolQ and Taq polymerase bound to DNA and compound 41.

EntireName: Chimera of PolQ and Taq polymerase bound to DNA and compound 41.
Components
  • Complex: Chimera of PolQ and Taq polymerase bound to DNA and compound 41.
    • Protein or peptide: PolQTaq chimera

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Supramolecule #1: Chimera of PolQ and Taq polymerase bound to DNA and compound 41.

SupramoleculeName: Chimera of PolQ and Taq polymerase bound to DNA and compound 41.
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: synthetic construct (others)

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Macromolecule #1: PolQTaq chimera

MacromoleculeName: PolQTaq chimera / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: ALEEAPWPPP EGAFVGFVLS RKEPMWADLL ALAAARGGRV HRAPEPYKAL RDLKEARGLL AKDLSVLALR EGL GLPPGD DPMLLAYLLD PSNTTPEGVA RRYGGEWTEE AGERAALSER L FANLWGRL EGEERLLWLY REVERPLSAV LAHMEATGVR LDVAYLRALS ...String:
ALEEAPWPPP EGAFVGFVLS RKEPMWADLL ALAAARGGRV HRAPEPYKAL RDLKEARGLL AKDLSVLALR EGL GLPPGD DPMLLAYLLD PSNTTPEGVA RRYGGEWTEE AGERAALSER L FANLWGRL EGEERLLWLY REVERPLSAV LAHMEATGVR LDVAYLRALS LEVAEEIARL EAEVFRLAGH PFNLN SRDQ LERVLFDELG LPAIGKTEKT GKRSTSAAVL EALREAHPIV EKI LQYREL TKLKSTYIDP LPDLIHPRTG RLHTRFNQTA TATGRLSSSD PNLQNIPVRT PLGQRIRRAF IAEEGWL LV ALDYSQLELR ILAHLSHDRR LIQVLNTGAD VFRSIAAEWK MIEPE SVGD DLRQQAKQIC YGIIYGMGAK SLGEQMGIKE NDAACYIDSF KSRYTGINQF MTETVKNCKR DGFVQTILG RRRYLPGIKD NNPYRKAHAE RQAINTIVQG SAADIMKLAM VKLFPRL EE MGARMLLQVH DELVLEAPKE RAEAVARLAK EVMEGVYPLA VPLEVEVGIG EDWLSAKE

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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: 7.5
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: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: cryoSPARC ab-initio
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 146091
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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