Structural basis for a Polθ helicase small-molecule inhibitor revealed by cryo-EM.

Autor: Ito F; Molecular and Computational Biology, Department of Biological Sciences and Chemistry, University of Southern California, Los Angeles, California, CA, 90089, USA., Li Z; Molecular and Computational Biology, Department of Biological Sciences and Chemistry, University of Southern California, Los Angeles, California, CA, 90089, USA., Minakhin L; Department of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA., Chandramouly G; Department of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA., Tyagi M; Department of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA., Betsch R; Nuclear Dynamics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA., Krais JJ; Nuclear Dynamics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA., Taberi B; Department of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA., Vekariya U; Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA., Calbert M; Department of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA., Skorski T; Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA., Johnson N; Nuclear Dynamics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA., Chen XS; Molecular and Computational Biology, Department of Biological Sciences and Chemistry, University of Southern California, Los Angeles, California, CA, 90089, USA. xiaojiac@usc.edu., Pomerantz RT; Department of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA. richard.pomerantz@jefferson.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Aug 14; Vol. 15 (1), pp. 7003. Date of Electronic Publication: 2024 Aug 14.
DOI: 10.1038/s41467-024-51351-4
Abstrakt: 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 50 against Polθ-hel, selectively kills BRCA1/2-deficient cells, and acts synergistically with olaparib in cancer cells harboring pathogenic BRCA1/2 mutations. Cryo-EM uncovers predominantly dimeric Polθ-hel:AB25583 complex structures at 3.0-3.2 Å. The structures reveal a binding-pocket deep inside the helicase central-channel, which underscores the high specificity and potency of AB25583. The cryo-EM structures in conjunction with biochemical data indicate that AB25583 inhibits the ATPase activity of Polθ-hel helicase via an allosteric mechanism. These detailed structural data and insights about AB25583 inhibition pave the way for accelerating drug development targeting Polθ-hel in HDR-deficient cancers.
(© 2024. The Author(s).)
Databáze: MEDLINE
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