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- PDB-9osy: Tetrameric POLQ Helicase-like Domain Bound to Cmpd 36, a Small-Mo... -

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Basic information

Entry
Database: PDB / ID: 9osy
TitleTetrameric POLQ Helicase-like Domain Bound to Cmpd 36, a Small-Molecule ATPase Inhibitor and Drug Candidate Analog
ComponentsDNA polymerase theta
KeywordsDNA BINDING PROTEIN / Theta-mediated end-joining DNA-dependent ATPase DNA repair Inhibitor co-complex
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsZahn, K.E. / Mader, P. / Sicheri, F.
Funding support1items
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, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 17, 2025Provider: repository / Type: Initial release
Revision 1.1Oct 1, 2025Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: DNA polymerase theta
B: DNA polymerase theta
C: DNA polymerase theta
D: DNA polymerase theta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)405,7428
Polymers403,5394
Non-polymers2,2024
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
DNA polymerase theta / DNA polymerase eta


Mass: 100884.812 Da / Num. of mol.: 4 / Fragment: N-terminal domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: POLQ, POLH / Production host: Escherichia coli (E. coli)
References: UniProt: O75417, DNA helicase, DNA-directed DNA polymerase, RNA-directed DNA polymerase
#2: Chemical
ChemComp-A1CEQ / (2P)-N-[5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl]-2-[2-(difluoromethyl)-5-methoxypyridin-4-yl]-4-[(4-hydroxyoxan-4-yl)ethynyl]benzamide


Mass: 550.576 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C28H24F2N4O4S / Feature type: SUBJECT OF INVESTIGATION
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: Polymerase theta N-terminal domain in complex with ATPase inhibitor compound
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.4 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
Details: 20 mM HEPES pH 7.5, 300 mM NaCl, 1 mM TCEP, 5% glycerol
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: POLQ-ATPase + RP-12068 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
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.

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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: 105000 X / Nominal defocus max: 1500 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 53 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of real images: 5769

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Processing

EM software
IDNameVersionCategoryDetails
1cryoSPARC3.1particle selectionTopaz was used to select particles
2Leginonimage acquisition
7Cootmodel fitting
13PHENIX1.19.2_4158model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionDetails: ~2.5M particles were initially selected from 4985 manually curated micrographs using cryoSPARC 3.1 live. All subsequent data processing was carried out in cryoSPARC 3.1.These particles were ...Details: ~2.5M particles were initially selected from 4985 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 4985 micrographs, yielding a new particle set comprising 387k particles.
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 387000 / Symmetry type: POINT
Atomic model buildingB value: 112.5 / Protocol: FLEXIBLE FIT / Space: REAL / Target criteria: CC_mask: 0.7952
Atomic model buildingPDB-ID: 5AGA

5aga


Accession code: 5AGA / Source name: PDB / Type: experimental model
RefinementHighest resolution: 2.9 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00321528
ELECTRON MICROSCOPYf_angle_d0.49829132
ELECTRON MICROSCOPYf_dihedral_angle_d8.0682924
ELECTRON MICROSCOPYf_chiral_restr0.0373444
ELECTRON MICROSCOPYf_plane_restr0.0033624

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