3U9Y

Crystal structure of human tankyrase 2 catalytic domain in complex with olaparib

3U9Y の概要

• エントリーDOI: 10.2210/pdb3u9y/pdb
• 関連するPDBエントリー: 3U9H 3UA9
• 分子名称: Tankyrase-2, ZINC ION, SULFATE ION, ... (6 entities in total)
• 機能のキーワード: protein-ligand complex, diphtheria toxin like fold, adp-ribosylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 28083.86

構造登録者

Narwal, M.,Lehtio, L. (登録日: 2011-10-20, 公開日: 2012-01-25, 最終更新日: 2023-09-13)

主引用文献

Narwal, M.,Venkannagari, H.,Lehtio, L.
Structural basis of selective inhibition of human tankyrases.
J.Med.Chem., 55:1360-1367, 2012

PubMed Abstract: Tankyrases are poly(ADP-ribose) polymerases that have many cellular functions. They play pharmaceutically important roles, at least in telomere homeostasis and Wnt signaling, by covalently ADP-ribosylating target proteins and consequently regulating their functions. These features make tankyrases potential targets for treatment of cancer. We report here crystal structures of human tankyrase 2 catalytic fragment in complex with a byproduct, nicotinamide, and with selective inhibitors of tankyrases (IWR-1) and PARPs 1 and 2 (olaparib). Binding of these inhibitors to tankyrase 2 induces specific conformational changes. The crystal structures explain the selectivity of the inhibitors, reveal the flexibility of a substrate binding loop, and explain existing structure-activity relationship data. The first crystal structure of a PARP enzyme in complex with a potent inhibitor, IWR-1, that does not bind to the widely utilized nicotinamide-binding site makes the structure valuable for development of PARP inhibitors in general.

PubMed: 22233320
DOI: 10.1021/jm201510p

実験手法

X-RAY DIFFRACTION (2.3 Å)