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 3
(a) Stereoview of the crystal structure of the TNKS2–ABT-888 complex (magenta) superimposed with the structure of PARP2–ABT-888 (gray; PDB entry 3jkd; Karlberg, Hammarström et al., 2010

). (b) The TNKS2 active-site cleft consists of a donor site (NAD⁺ site) and an acceptor site. The left panel illustrates the closed conformation of the TNKS2 PARP domain. The side chain of Tyr1050 from the D-loop divides the acceptor site and the NAD⁺ site. The NAD⁺ site can be further divided into the NI-subsite (where the nicotinamide group is located) and the AD-subsite (which is occupied by the adenosine moiety of NAD⁺). The right panel represents the opened conformation of the TNKS2 PARP domain, in which the side chain of Tyr1050 swings away from the center of the active site and makes the deeply buried NI-subsite widely accessible. (c) Close-up view of the NI-subsite of TNKS2 in complex with 3-AB (magenta) and TIQ-A (cyan). The side chain of Tyr1050 from the TNKS2–TIQ-A complex is in the closed confirmation compared with the open conformation of the same residue in the TNKS2–3-AB complex. Also, as shown on the far left of the figure, three conserved cysteine residues and one histidine form a short zinc-binding motif involved in the chelation of Zn²⁺.

STRUCTURAL
BIOLOGY

ISSN: 2059-7983

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

https://doi.org/10.1107/S1399004714017660

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