6N19

Crystal structure of Tdp1 catalytic domain in complex with compound XZ578

6N19 の概要

• エントリーDOI: 10.2210/pdb6n19/pdb
• 分子名称: Tyrosyl-DNA phosphodiesterase 1, 4-[(4-carboxybutanoyl)amino]benzene-1,2-dicarboxylic acid, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: fragment based drug design, anti-cancer drug design, dna binding protein, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 105029.37

構造登録者

Lountos, G.T.,Zhao, X.Z.,Kiselev, E.,Tropea, J.E.,Needle, D.,Burke Jr., T.R.,Pommier, Y.,Waugh, D.S. (登録日: 2018-11-08, 公開日: 2019-07-03, 最終更新日: 2023-10-11)

主引用文献

Lountos, G.T.,Zhao, X.Z.,Kiselev, E.,Tropea, J.E.,Needle, D.,Pommier, Y.,Burke, T.R.,Waugh, D.S.
Identification of a ligand binding hot spot and structural motifs replicating aspects of tyrosyl-DNA phosphodiesterase I (TDP1) phosphoryl recognition by crystallographic fragment cocktail screening.
Nucleic Acids Res., 47:10134-10150, 2019

PubMed Abstract: Tyrosyl DNA-phosphodiesterase I (TDP1) repairs type IB topoisomerase (TOP1) cleavage complexes generated by TOP1 inhibitors commonly used as anticancer agents. TDP1 also removes DNA 3' end blocking lesions generated by chain-terminating nucleosides and alkylating agents, and base oxidation both in the nuclear and mitochondrial genomes. Combination therapy with TDP1 inhibitors is proposed to synergize with topoisomerase targeting drugs to enhance selectivity against cancer cells exhibiting deficiencies in parallel DNA repair pathways. A crystallographic fragment screening campaign against the catalytic domain of TDP1 was conducted to identify new lead compounds. Crystal structures revealed two fragments that bind to the TDP1 active site and exhibit inhibitory activity against TDP1. These fragments occupy a similar position in the TDP1 active site as seen in prior crystal structures of TDP1 with bound vanadate, a transition state mimic. Using structural insights into fragment binding, several fragment derivatives have been prepared and evaluated in biochemical assays. These results demonstrate that fragment-based methods can be a highly feasible approach toward the discovery of small-molecule chemical scaffolds to target TDP1, and for the first time, we provide co-crystal structures of small molecule inhibitors bound to TDP1, which could serve for the rational development of medicinal TDP1 inhibitors.

PubMed: 31199869
DOI: 10.1093/nar/gkz515

実験手法

X-RAY DIFFRACTION (1.501 Å)