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TitleStructural basis for a Polθ helicase small-molecule inhibitor revealed by cryo-EM.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 7003, Year 2024
Publish dateAug 14, 2024
AuthorsFumiaki Ito / Ziyuan Li / Leonid Minakhin / Gurushankar Chandramouly / Mrityunjay Tyagi / Robert Betsch / John J Krais / Bernadette Taberi / Umeshkumar Vekariya / Marissa Calbert / Tomasz Skorski / Neil Johnson / Xiaojiang S Chen / Richard T Pomerantz /
PubMed AbstractDNA 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 ...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 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.
External linksNat Commun / PubMed:39143110 / PubMed Central
MethodsEM (single particle)
Resolution3.21 Å
Structure data

44765

9bp9

EMDB-44765, PDB-9bp9:
Human DNA polymerase theta helicase domain in complex with inhibitor AB25583, dimer form
Method: EM (single particle) / Resolution: 3.21 Å

44766

9bpa

EMDB-44766, PDB-9bpa:
Human DNA polymerase theta helicase domain in complex with inhibitor AB25583, tetramer form
Method: EM (single particle) / Resolution: 3.21 Å

Chemicals


ChemComp, No image

ChemComp-WCN:
Unknown entry

Source
  • homo sapiens (human)
KeywordsTRANSFERASE/INHIBITOR / DNA repair / helicase / ATPase / TRANSFERASE-INHIBITOR complex

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