Fig. 3: Structural basis of Polθ-pol inhibition.
From: Discovery of a small-molecule inhibitor that traps Polθ on DNA and synergizes with PARP inhibitors
a Overall structure of PolθΔL:DNA/DNA:ddGTP:RTx-152. b Left side of figure is a 2D ligand plot map detailing the interactions between inhibitor RTx-152 and the surrounding allosteric pocket. Hydrophobic contacts are shown by the red radiating symbols while the hydrogen bond between Y2420 and O20 of RTx-152 is shown by a green dashed line. The right side of the figure is a 3D model in PyMOL detailing the position of each of the residues shown on the left within the allosteric binding site in relation to RTx-152. c Electrostatic surface representation of PolθΔL at the allosteric inhibitor binding site. Positive potential is in blue, negative potential is in red, and neutral in white. d 3D structure of the allosteric binding pocket of both the previously published closed conformations of Polθ-pol (PDB 4x0q, in magenta) and that of the PolθΔL RTx-152 inhibitor complex in this study (in green). Shown here and in (e–g) are differences in key residues due to the induced fit mechanism of the binding of RTx-152. e RTx-152 binding to the pocket induced Y2412 switch to form pi stacking, which in turn to induce W2366 switch to form a hydrophobic packing. f RTx-152 binding induced the conformational switch of E2365 and R2419 to form a salt bridge across surface of the binding pocket. g The bound RTx-152 engages key residues such as Y2412, F2416 and Y2420 on alpha helix O2, forming pi stacking with Y2412 and F2416 and a hydrogen bond with Y2420. h Overlap of the allosteric RTx-152-binding pockets between the open and closed conformations of PolθΔL, showing that the pocket in the closed state is not present in the open state.
