8GD7
Loop Deleted DNA Polymerase Theta Polymerase Domain in Complex with Double Strand DNA Overhang and Inhibitor
Summary for 8GD7
| Entry DOI | 10.2210/pdb8gd7/pdb |
| Descriptor | DNA polymerase theta, DNA Template, DNA Primer, ... (6 entities in total) |
| Functional Keywords | dna polymerase theta, inhibitor, dna binding protein, dna binding protein-dna complex, dna binding protein/dna |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 3 |
| Total formula weight | 85224.14 |
| Authors | |
| Primary citation | Fried, W.,Tyagi, M.,Minakhin, L.,Chandramouly, G.,Tredinnick, T.,Ramanjulu, M.,Auerbacher, W.,Calbert, M.,Rusanov, T.,Hoang, T.,Borisonnik, N.,Betsch, R.,Krais, J.J.,Wang, Y.,Vekariya, U.M.,Gordon, J.,Morton, G.,Kent, T.,Skorski, T.,Johnson, N.,Childers, W.,Chen, X.S.,Pomerantz, R.T. Discovery of a small-molecule inhibitor that traps Pol theta on DNA and synergizes with PARP inhibitors. Nat Commun, 15:2862-2862, 2024 Cited by PubMed Abstract: The DNA damage response (DDR) protein DNA Polymerase θ (Polθ) is synthetic lethal with homologous recombination (HR) factors and is therefore a promising drug target in BRCA1/2 mutant cancers. We discover an allosteric Polθ inhibitor (Polθi) class with 4-6 nM IC that selectively kills HR-deficient cells and acts synergistically with PARP inhibitors (PARPi) in multiple genetic backgrounds. X-ray crystallography and biochemistry reveal that Polθi selectively inhibits Polθ polymerase (Polθ-pol) in the closed conformation on B-form DNA/DNA via an induced fit mechanism. In contrast, Polθi fails to inhibit Polθ-pol catalytic activity on A-form DNA/RNA in which the enzyme binds in the open configuration. Remarkably, Polθi binding to the Polθ-pol:DNA/DNA closed complex traps the polymerase on DNA for more than forty minutes which elucidates the inhibitory mechanism of action. These data reveal a unique small-molecule DNA polymerase:DNA trapping mechanism that induces synthetic lethality in HR-deficient cells and potentiates the activity of PARPi. PubMed: 38580648DOI: 10.1038/s41467-024-46593-1 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.24 Å) |
Structure validation
Download full validation report
