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![[Figure 4]](lv5074fig4mag.jpg)
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Figure 4
(a) The structure of the TNKS2 PARP domain in complex with the first-generation inhibitor 3-AB. 3-AB binds on the bottom of the active site, mimicking the binding mode of nicotinamide. It forms three conserved hydrogen bonds to the backbone of Gly1032 and the side chain of Ser1068. The benzamide ring of 3-AB is in the approximate position to form a π-stacking interaction with Tyr1071. The 3′ amide of 3-AB forms a connection with the catalytically important residue Glu1138 through a well defined isopropanol molecule (IPA) from the crystallization conditions. The electron density around the inhibitor is a σ-weighted 2mFo − DFc map contoured at 1σ. (b) The B ring of DR-2313 forms three conserved hydrogen bonds to Gly1032 and Ser1068 and a π-stacking interaction with Tyr1071. The A ring also displays hydrophobic interactions with the catalytically important Glu1138 as well as Tyr1060, Phe1061 and Lys1067. The DR-2313 molecule is represented in a stick form covered by spheres, with the S atom colored yellow. (c) NU-1025 forms three hydrogen bonds to Gly1032 and Ser1068 and the π-stacking interaction with Tyr1071 as well as a water-mediated hydrogen bond which links the hydroxyl group of the A ring to Glu1138. (d) 4-HQN forms three hydrogen bonds to Gly1032 and Ser1068 and the π-stacking interaction with Tyr1071. (e) 5-AIQ has similar interactions with TNKS2: three conserved hydrogen bonds to Gly1032 and Ser1068 and a π-stacking interaction with Tyr1071. (f) In addition to the conserved hydrogen bonds and π-stacking interaction, 1,5-IQD makes another water-mediated hydrogen bond from the hydroxyl group of the A ring to Glu1138. (g) TIQ-A forms four hydrogen bonds to TNKS2. The B ring forms three hydrogen bonds to the backbone of Gly1032 and one to the side chain of Ser1068. The tricyclic ring of TIQ-A accounts for a larger planar surface and forms a π-stacking interaction with Tyr1071 compared with the other one-ring or two-ring inhibitors from the same inhibitor class. The side chain of Tyr1050 from the D-loop also swings towards TIQ-A and adopts a closed conformation. (h) INH2BP binds to the NI-subsite differently from the other PARP inhibitors observed in this study. The inhibitor adopts a position in which the iodine moiety points towards the AD-subsite. It does not preserve the three critical hydrogen bonds on the bottom of the NI-subsite observed for 3-AB or TIQ-A. Instead, the hydroxyl group forms only two hydrogen bonds to the main chain of Gly1032 and the side chain of Ser1068. |
![[Figure 4]](lv5074fig4.jpg)
 | STRUCTURAL BIOLOGY |
ISSN: 2059-7983
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