Insights into the binding of PARP inhibitors to the catalytic domain of human tankyrase-2

Qiu, W.; Lam, R.; Voytyuk, O.; Romanov, V.; Gordon, R.; Gebremeskel, S.; Vodsedalek, J.; Thompson, C.; Beletskaya, I.; Battaile, K.P.; Pai, E.F.; Rottapel, R.; Chirgadze, N.Y.

doi:10.1107/S1399004714017660

Figure 5
(a) The tricyclic lactam core of PJ-34 provides multiple contacts within the NI-subsite, with three conserved hydrogen bonds and extended π-sandwich stacking from Tyr1060 and Tyr1071. Unlike the closed conformation observed in the TIQ-A structure (Fig. 4

g), the tertiary amine extension of PJ-34 pushes the D-loop away from the NAD⁺ site and the side chain of Tyr1050 adopts an open conformation. (b) The binding features of ABT-888 with TNKS2 compared with the PARP2 catalytic domains. The pyrrolidine ring of ABT-888 is rotated about 10° towards Glu1138 in the TNKS2 structure compared with its position in the PARP2 complex, with a largest shift of 1.7 Å between the two ABT-888 molecules. At the base of the NI-subsite, the carboxamidyl moiety forms three hydrogen bonds to the backbone of Gly1032 and the side chain of Ser1068 in both TNKS2 and PARP2 (the residue numbering is different in PARP2). The N3 atom of the benzimidazole forms a water-mediated hydrogen bond to Glu1138 in the TNKS2 complex (colored magenta), while the N2 atom of the ABT-888 pyrrolidine forms a water-mediated interaction with a glutamate from the N-terminal helix-bundle domain in the PARP2 complex (colored gray). (d) The isoquinolinone base of DPQ contributes to most of the interactions between the inhibitor and TNKS2, with three conserved hydrogen bonds to Gly1032 and Ser1068 as well as π-stacking with Tyr1071 and Tyr1060.

STRUCTURAL
BIOLOGY

ISSN: 2059-7983

Volume 70| Part 10| October 2014| Pages 2740-2753

https://doi.org/10.1107/S1399004714017660

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