Kirby Christina A, Cheung Atwood, Fazal Aleem, Shultz Michael D, Stams Travis
Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA.
Acta Crystallogr Sect F Struct Biol Cryst Commun. 2012 Feb 1;68(Pt 2):115-8. doi: 10.1107/S1744309111051219. Epub 2012 Jan 21.
The crystal structures of tankyrase 1 (TNKS1) in complex with two small-molecule inhibitors, PJ34 and XAV939, both at 2.0 Å resolution, are reported. The structure of TNKS1 in complex with PJ34 reveals two molecules of PJ34 bound in the NAD(+) donor pocket. One molecule is in the nicotinamide portion of the pocket, as previously observed in other PARP structures, while the second molecule is bound in the adenosine portion of the pocket. Additionally, unlike the unliganded crystallization system, the TNKS1-PJ34 crystallization system has the NAD(+) donor site accessible to bulk solvent in the crystal, which allows displacement soaking. The TNKS1-PJ34 crystallization system was used to determine the structure of TNKS1 in complex with XAV939. These structures provide a basis for the start of a structure-based drug-design campaign for TNKS1.
报道了端锚聚合酶1（TNKS1）与两种小分子抑制剂PJ34和XAV939复合物的晶体结构，分辨率均为2.0 Å。TNKS1与PJ34复合物的结构显示，两个PJ34分子结合在NAD(+)供体口袋中。一个分子位于口袋的烟酰胺部分，如先前在其他PARP结构中观察到的那样，而第二个分子则结合在口袋的腺苷部分。此外，与未结合配体的结晶系统不同，TNKS1-PJ34结晶系统在晶体中使NAD(+)供体位点可被大量溶剂接触，这允许进行置换浸泡。TNKS1-PJ34结晶系统用于确定TNKS1与XAV939复合物的结构。这些结构为开展基于结构的TNKS1药物设计活动奠定了基础。
