Fig 2: Olaparib energetics when bound to PARP1 or TNKS1. The two olaparib conformational states (bound to PARP1 in green and bound to TNKS1 in orange) are superposed on top. The energy profiles of two torsion angles are shown, which have lower energy in the PARP1-bound conformation (green, left), relative to the TNKS1-bound conformation (orange, right). The torsional energies of the other rotatable bonds are very similar in the two conformers. PARP1, poly(ADP-ribosyl) polymerase 1; TNKS1, tankyrase1.

Fig 3: Talazoparib makes a favorable interaction with the structurally conserved water molecule in poly(ADP-ribosyl) polymerase 1 (PARP1) and tankyrase1 (TNKS1) catalytic domains. The structural water molecule is shown as red sphere. A, PARP1 recognition of talazoparib. B, TNKS1 recognition of talazoparib.

Fig 4: Overall structures of the catalytic domain of poly(ADP-ribosyl) polymerase 1 (PARP1) and the ART domain of tankyrase1 (TNKS1) and similarities in the ligand-binding sites.A, PARP1 catalytic domain is composed of the helical domain and ART domain. B, TNKS1 ART domain. The broken line shows the disordered region of TNKS1 D-loop that is not modeled due to the absence of electron density. Recognition of talazoparib by (C) PARP1 and (D) TNKS1 is similar in the two proteins. ART, ADP-ribosyltransferase; D-loop, donor loop.

Fig 5: Niraparib energetics when bound to PARP1 (green) or TNKS1 (orange). The two niraparib conformational states (bound to PARP1 in green and bound to TNKS1 in orange) are superposed on top. The energy profiles of two torsion angles are shown at the bottom. The torsion angle between the phenyl ring and the piperidine is clearly more favorable energetically in the PARP1-bound conformation (green, left), relative to the TNKS1-bound conformation (orange, right). The torsional energies of the other rotatable bonds are very similar in the two conformers. PARP1, poly(ADP-ribosyl) polymerase 1; TNKS1, tankyrase1.