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- EMDB-70812: Tetrameric POLQ Helicase-like Domain Bound to Cmpd 19, a Small-Mo... -

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Entry
Database: EMDB / ID: EMD-70812
TitleTetrameric POLQ Helicase-like Domain Bound to Cmpd 19, a Small-Molecule ATPase Inhibitor and Drug Candidate Analog
Map dataSharpened map
Sample
  • Complex: Polymerase theta N-terminal domain in complex with ATPase inhibitor compound
    • Protein or peptide: DNA polymerase theta
  • Ligand: (3M)-2'-chloro-N-{5-[(1S,2S)-2-(4-cyanophenyl)cyclopropyl]-1,3,4-thiadiazol-2-yl}-5'-methoxy[3,4'-bipyridine]-4-carboxamide
KeywordsTheta-mediated end-joining DNA-dependent ATPase DNA repair Inhibitor co-complex / DNA BINDING PROTEIN
Function / homology
Function and homology information


double-strand break repair via alternative nonhomologous end joining / HDR through MMEJ (alt-NHEJ) / single-stranded DNA helicase activity / replication fork processing / mitochondrial nucleoid / site of DNA damage / 5'-deoxyribose-5-phosphate lyase activity / error-prone translesion synthesis / negative regulation of double-strand break repair via homologous recombination / somatic hypermutation of immunoglobulin genes ...double-strand break repair via alternative nonhomologous end joining / HDR through MMEJ (alt-NHEJ) / single-stranded DNA helicase activity / replication fork processing / mitochondrial nucleoid / site of DNA damage / 5'-deoxyribose-5-phosphate lyase activity / error-prone translesion synthesis / negative regulation of double-strand break repair via homologous recombination / somatic hypermutation of immunoglobulin genes / DNA helicase activity / base-excision repair / protein homooligomerization / RNA-directed DNA polymerase / RNA-directed DNA polymerase activity / double-strand break repair / site of double-strand break / DNA helicase / DNA-directed DNA polymerase / damaged DNA binding / DNA-directed DNA polymerase activity / DNA repair / DNA damage response / chromatin binding / magnesium ion binding / Golgi apparatus / ATP hydrolysis activity / nucleoplasm / ATP binding / identical protein binding / nucleus / cytosol
Similarity search - Function
: / : / DNA_pol_Q helicase like region helical domain / Domain of unknown function (DUF7898) / DNA polymerase theta-like, helix-turn-helix domain / Helix-turn-helix domain / DNA polymerase A / DNA polymerase family A / DNA-directed DNA polymerase, family A, conserved site / DNA polymerase family A signature. ...: / : / DNA_pol_Q helicase like region helical domain / Domain of unknown function (DUF7898) / DNA polymerase theta-like, helix-turn-helix domain / Helix-turn-helix domain / DNA polymerase A / DNA polymerase family A / DNA-directed DNA polymerase, family A, conserved site / DNA polymerase family A signature. / DNA-directed DNA polymerase, family A, palm domain / DNA polymerase A domain / DEAD/DEAH box helicase domain / DEAD/DEAH box helicase / Helicase conserved C-terminal domain / helicase superfamily c-terminal domain / Superfamilies 1 and 2 helicase C-terminal domain profile. / Superfamilies 1 and 2 helicase ATP-binding type-1 domain profile. / DEAD-like helicases superfamily / Helicase, C-terminal / Helicase superfamily 1/2, ATP-binding domain / Ribonuclease H superfamily / Ribonuclease H-like superfamily / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
DNA polymerase theta
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.67 Å
AuthorsZahn KE / Scapin G
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: J Med Chem / Year: 2025
Title: The Discovery of RP-2119: A Potent, Selective, and Orally Bioavailable Polθ ATPase Inhibitor.
Authors: Philippe Mochirian / Robert Papp / Marie-Claude Mathieu / Gino B Ferraro / Evelyne Dietrich / Bingcan Liu / David Bendahan / Alexander L Perryman / Simon Surprenant / Sara Fournier / Bita ...Authors: Philippe Mochirian / Robert Papp / Marie-Claude Mathieu / Gino B Ferraro / Evelyne Dietrich / Bingcan Liu / David Bendahan / Alexander L Perryman / Simon Surprenant / Sara Fournier / Bita Lotfollahzadeh Barzili / Alexanne Bonneau-Fortin / Shou Yun Yin / Marie-Eve Leclaire / Charmi Patel / Hugo Poirier / Sai Save / Yann Mathieu / Nicolas Morin / Claude Godbout / Helen E Burston / Karl E Zahn / Mohamed A Attia / Thomas Pinter / Francis Barabé / Paranjay Parikh / Chandresh Jagani / Gyunghoon Kang / Giovanna Scapin / Yael Mamane / Agnel Sfeir / Pavel Mader / Frank Sicheri / Michal Zimmermann / Anne Roulston / Stephen J Morris / W Cameron Black / Michel Gallant /
Abstract: DNA polymerase theta (Polθ) plays a critical role in repairing DNA double-strand breaks through microhomology-mediated end joining (MMEJ) and has emerged as a key synthetic lethal drug target in ...DNA polymerase theta (Polθ) plays a critical role in repairing DNA double-strand breaks through microhomology-mediated end joining (MMEJ) and has emerged as a key synthetic lethal drug target in cancers with homologous recombination (HR) deficiencies. Its inhibition has shown a strong potential to synergize with PARP inhibitors, particularly in tumors with deleterious or mutations. Here, we describe the discovery and preclinical development of RP-2119, a selective, potent, and bioavailable Polθ ATPase inhibitor. Starting from a high-throughput ATPase screen combined with literature insights, key vectors for enhancing potency were identified by structural studies using single-particle cryo-electron microscopy (cryo-EM) that revealed the inhibitor binding site. Further optimization of potency and ADME properties led to the identification of RP-2119 with robust cellular activity in a wide range of HR-deficient cancer cell lines. In HR-deficient cell line- and patient-derived mouse xenografts, RP-2119 demonstrated strong synergy with the PARP inhibitor, olaparib, without exacerbating its hematological toxicity.
History
DepositionMay 26, 2025-
Header (metadata) releaseSep 17, 2025-
Map releaseSep 17, 2025-
UpdateOct 1, 2025-
Current statusOct 1, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70812.png

Downloads & links

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Map

FileDownload / File: emd_70812.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 360 pix.
= 297. Å		0.83 Å/pix.
x 360 pix.
= 297. Å		0.83 Å/pix.
x 360 pix.
= 297. Å

Surface

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.825 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.085
Minimum - Maximum-0.6619957 - 1.1047114
Average (Standard dev.)0.00047776726 (±0.024284532)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 297.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: For the unsharpened map, a contour level of...

Fileemd_70812_additional_1.map
AnnotationFor the unsharpened map, a contour level of was selected to enclose a similar molecular volume, based on visual inspection and volumetric measurement in UCSF Chimera.
Projections & Slices
AxesZYX

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Histogram

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Half map: Half map A

Fileemd_70812_half_map_1.map
AnnotationHalf map A
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: Half map B

Fileemd_70812_half_map_2.map
AnnotationHalf map B
Projections & Slices
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Sample components

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Entire : Polymerase theta N-terminal domain in complex with ATPase inhibit...

EntireName: Polymerase theta N-terminal domain in complex with ATPase inhibitor compound
Components
  • Complex: Polymerase theta N-terminal domain in complex with ATPase inhibitor compound
    • Protein or peptide: DNA polymerase theta
  • Ligand: (3M)-2'-chloro-N-{5-[(1S,2S)-2-(4-cyanophenyl)cyclopropyl]-1,3,4-thiadiazol-2-yl}-5'-methoxy[3,4'-bipyridine]-4-carboxamide

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Supramolecule #1: Polymerase theta N-terminal domain in complex with ATPase inhibit...

SupramoleculeName: Polymerase theta N-terminal domain in complex with ATPase inhibitor compound
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 400 KDa

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Macromolecule #1: DNA polymerase theta

MacromoleculeName: DNA polymerase theta / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO / EC number: DNA helicase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 100.884812 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MNLLRRSGKR RRSESGSDSF SGSGGDSSAS PQFLSGSVLS PPPGLGRCLK AAAAGECKPT VPDYERDKLL LANWGLPKAV LEKYHSFGV KKMFEWQAEC LLLGQVLEGK NLVYSAPTSA GKTLVAELLI LKRVLEMRKK ALFILPFVSV AKEKKYYLQS L FQEVGIKV ...String:
MNLLRRSGKR RRSESGSDSF SGSGGDSSAS PQFLSGSVLS PPPGLGRCLK AAAAGECKPT VPDYERDKLL LANWGLPKAV LEKYHSFGV KKMFEWQAEC LLLGQVLEGK NLVYSAPTSA GKTLVAELLI LKRVLEMRKK ALFILPFVSV AKEKKYYLQS L FQEVGIKV DGYMGSTSPS RHFSSLDIAV CTIERANGLI NRLIEENKMD LLGMVVVDEL HMLGDSHRGY LLELLLTKIC YI TRKSASC QADLASSLSN AVQIVGMSAT LPNLELVASW LNAELYHTDF RPVPLLESVK VGNSIYDSSM KLVREFEPML QVK GDEDHV VSLCYETICD NHSVLLFCPS KKWCEKLADI IAREFYNLHH QAEGLVKPSE CPPVILEQKE LLEVMDQLRR LPSG LDSVL QKTVPWGVAF HHAGLTFEER DIIEGAFRQG LIRVLAATST LSSGVNLPAR RVIIRTPIFG GRPLDILTYK QMVGR AGRK GVDTVGESIL ICKNSEKSKG IALLQGSLKP VRSCLQRREG EEVTGSMIRA ILEIIVGGVA STSQDMHTYA ACTFLA ASM KEGKQGIQRN QESVQLGAIE ACVMWLLENE FIQSTEASDG TEGKVYHPTH LGSATLSSSL SPADTLDIFA DLQRAMK GF VLENDLHILY LVTPMFEDWT TIDWYRFFCL WEKLPTSMKR VAELVGVEEG FLARCVKGKV VARTERQHRQ MAIHKRFF T SLVLLDLISE VPLREINQKY GCNRGQIQSL QQSAAVYAGM ITVFSNRLGW HNMELLLSQF QKRLTFGIQR ELCDLVRVS LLNAQRARVL YASGFHTVAD LARANIVEVE VILKNAVPFK SARKAVDEEE EAVEERRNMR TIWVTGRKGL TEREAAALIV EEARMILQQ DLVEMGVQWN PCALL

UniProtKB: DNA polymerase theta

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Macromolecule #2: (3M)-2'-chloro-N-{5-[(1S,2S)-2-(4-cyanophenyl)cyclopropyl]-1,3,4-...

MacromoleculeName: (3M)-2'-chloro-N-{5-[(1S,2S)-2-(4-cyanophenyl)cyclopropyl]-1,3,4-thiadiazol-2-yl}-5'-methoxy[3,4'-bipyridine]-4-carboxamide
type: ligand / ID: 2 / Number of copies: 4 / Formula: A1CER
Molecular weightTheoretical: 488.949 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

Concentration1.0 mg/mL
BufferpH: 7.5
Details: 20 mM HEPES pH 7.5, 300 mM NaCl, 1 mM TCEP, 5% glycerol
GridModel: UltrAuFoil / Pretreatment - Type: PLASMA CLEANING
VitrificationCryogen name: ETHANE
Details: 3 microL drop of sample suspension is applied to an EM grid that has been plasma-cleaned using a Gatan Solarus. After blotting the sample away with filter paper, grids are plunge-frozen in ...Details: 3 microL drop of sample suspension is applied to an EM grid that has been plasma-cleaned using a Gatan Solarus. After blotting the sample away with filter paper, grids are plunge-frozen in liquid ethane. Grids are stored under liquid nitrogen until transferred to the transmission electron microscope for imaging..
DetailsPOLQ-ATPase + RP-11203 compound were mixed on ice in buffer to a final concentration of 1.00 mg/mL protein and 2x molar equivalents of the inhibitor compound

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number real images: 15749 / 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: 1.8 µm / Nominal defocus min: 1.2 µm / Nominal magnification: 105000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionDetails: ~14.5M particles were initially selected from 14,375 manually curated micrographs using cryoSPARC 3.1 live. All subsequent data processing was carried out in cryoSPARC 3.1.These particles ...Details: ~14.5M particles were initially selected from 14,375 manually curated micrographs using cryoSPARC 3.1 live. All subsequent data processing was carried out in cryoSPARC 3.1.These particles were subjected to 3 rounds of 2D classification. A subset of particles from the final round of 2D classification were used to train the Deep Learning particle picker Topaz (as implemented in cryoSPARC 3.1). The Topaz trained model was used to re-extract particles from the 14,375 micrographs, yielding a new particle set comprising ~7M particles.
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

5aga

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.67 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 674000
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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Atomic model buiding 1

Initial modelPDB ID:

5aga


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Overall B value: 76.4 / Target criteria: CC_mask: 0.8076
Output model

PDB-9osw:
Tetrameric POLQ Helicase-like Domain Bound to Cmpd 19, a Small-Molecule ATPase Inhibitor and Drug Candidate Analog

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