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 6
(a) EB-47 occupies the entire NAD-binding pocket in a manner that mimics the binding mode of NAD⁺. The isoindolinone core interacts with the three conserved hydrogen bonds and a π-stacking effect of Tyr1060 and Tyr1071 can be observed. The adenosine moiety forms four hydrogen bonds to the surrounding protein residues, including an interaction between the hydroxyl group of the ribose and His1031 within the catalytic core. A network of water-mediated hydrogen bonds further enhances the interactions of the compound within the NAD⁺ donor site. (b) In complex with 3-AB, IWR-1 occupies the AD-subsite without perturbation of the NI-subsite. IWR-1 is stabilized in the AD-subsite primarily through hydrophobic interactions. The adenine ring experiences a π-sandwich stacking interaction between Phe1035 and His1048. The other aspect of the IWR-1 ring structure is its orientation into the hydrophobic pocket surrounded by the side chains of Ile1075, Tyr1071 and Tyr1060. Two additional hydrogen bonds are created to Asp1045. 3-AB is present in the co-crystal near the NI-subsite and contributes to the binding stability of the IWR-1 inhibitor and interacts with Tyr1071 through a π-sandwich stacking interaction, a hydrogen bond to Ser1068 and a water-mediated hydrogen bond to Glu1138. (c) The bicyclic ring of AZD-2281 binds in the NI-subsite by forming the three critical hydrogen bonds and a π-sandwich stacking interaction. The fluorobenzyl ring in the central position displaces the D-loop by forming a direct hydrogen bond to the backbone of Phe1048. The carbonyl O atom next to the fluorobenzyl ring forms a direct hydrogen bond to the backbone of Tyr1060. Another carbonyl O atom close to the cyclopropyl ring forms one direct hydrogen bond to the backbone of Asp1045 and one water-mediated hydrogen bond to the backbone of Gly1043. The cyclopropyl ring sits in the AD-subsite in between the aromatic rings of Phe1035 and His1048. (d) BSI-201 forms a novel inhibited structure in which two molecules of BSI-201 bind at two distinct sites within the PARP domain of TNKS2. Molecule A of BSI-201 is located in the NI-subsite. The nitro group along with the iodine at the 4-position face towards the center of the protein. The nitro group forms three hydrogen bonds, two with Ser1068 and one with Gly1032, mimicking the function of an amide group. The side chains of Lys1067 and Glu1138 adjust themselves to accommodate the nonpolar interaction with the iodine ion. The amide group on the other side of NI-subsite forms a direct hydrogen bond to the main chain of Gly1032. It also contributes to three water-mediated hydrogen bonds to the main chain of Tyr1071, the main chain of Tyr1060 and the side chain of Ser1033. Another observation is that the side chain of Tyr1050 swings towards BSI-201a to close the NI-subsite in a manner similar to that observed in the TIQ-A complex structure (Figs. 4

a and 4

c). Tyr1050 also contributes to the hydrophobic environment for BSI-201a binding. Molecule B of BSI-201 is located in the AD-subsite. The majority of the binding entropy is derived from the π-stacking and nonpolar interactions, with one water-mediated hydrogen bond from the nitro group to the main chain of Asp1045.

STRUCTURAL
BIOLOGY

ISSN: 2059-7983

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

https://doi.org/10.1107/S1399004714017660

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