9bpa

Human DNA polymerase theta helicase domain in complex with inhibitor AB25583, tetramer form

spinqualitylabelsall models 9bpa, resolution 3.21Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9bpa is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.21Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DPOLQ_HUMAN Has a DNA polymerase activity on nicked double-stranded DNA and on a singly primed DNA template. The enzyme activity is resistant to aphidicolin, and inhibited by dideoxynucleotides. Exhibites a single-stranded DNA-dependent ATPase activity. Could be involved in the repair of interstrand cross-links. Publication Abstract from PubMed DNA polymerase theta (Poltheta) is a DNA helicase-polymerase protein that facilitates DNA repair and is synthetic lethal with homology-directed repair (HDR) factors. Thus, Poltheta is a promising precision oncology drug-target in HDR-deficient cancers. Here, we characterize the binding and mechanism of action of a Poltheta helicase (Poltheta-hel) small-molecule inhibitor (AB25583) using cryo-EM. AB25583 exhibits 6 nM IC(50) against Poltheta-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 Poltheta-hel:AB25583 complex structures at 3.0-3.2 A. 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 Poltheta-hel helicase via an allosteric mechanism. These detailed structural data and insights about AB25583 inhibition pave the way for accelerating drug development targeting Poltheta-hel in HDR-deficient cancers. Structural basis for a Poltheta helicase small-molecule inhibitor revealed by cryo-EM.,Ito F, Li Z, Minakhin L, Chandramouly G, Tyagi M, Betsch R, Krais JJ, Taberi B, Vekariya U, Calbert M, Skorski T, Johnson N, Chen XS, Pomerantz RT Nat Commun. 2024 Aug 14;15(1):7003. doi: 10.1038/s41467-024-51351-4. PMID:39143110 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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