Open AccessStructure of human tankyrase 1 in complex with small‐molecule inhibitors PJ34 and XAV939
Author(s) -
Kirby Christina A.,
Cheung Atwood,
Fazal Aleem,
Shultz Michael D.,
Stams Travis
Publication year - 2012
Publication title -
acta crystallographica section f
Language(s) - English
Resource type - Journals
ISSN - 1744-3091
DOI - 10.1107/s1744309111051219
Subject(s) - crystallization , molecule , crystallography , nad+ kinase , crystal structure , chemistry , enzyme , organic chemistry
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.