Cryo-EM micrographs of human DNA polymerase θ helicase domain bound to inhibitor AB25583
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ABSTRACT:
SUBMITTER: Fumiaki Ito
PROVIDER: EMPIAR-11711 | biostudies-other |
REPOSITORIES: biostudies-other
Publications
Structural basis for a Polθ helicase small-molecule inhibitor revealed by cryo-EM.
Ito Fumiaki F Li Ziyuan Z Minakhin Leonid L Chandramouly Gurushankar G Tyagi Mrityunjay M Betsch Robert R Krais John J JJ Taberi Bernadette B Vekariya Umeshkumar U Calbert Marissa M Skorski Tomasz T Johnson Neil N Chen Xiaojiang S XS Pomerantz Richard T RT
Nature communications 20240814 1
DNA polymerase theta (Polθ) is a DNA helicase-polymerase protein that facilitates DNA repair and is synthetic lethal with homology-directed repair (HDR) factors. Thus, Polθ is a promising precision oncology drug-target in HDR-deficient cancers. Here, we characterize the binding and mechanism of action of a Polθ helicase (Polθ-hel) small-molecule inhibitor (AB25583) using cryo-EM. AB25583 exhibits 6 nM IC<sub>50</sub> against Polθ-hel, selectively kills BRCA1/2-deficient cells, and acts synergist ...[more]
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