4IQV

Tdt core in complex with inhibitor 6-[4-(3-fluorobenzoyl)-1H-pyrrol-2-yl]-2-hydroxy-4-oxohexa-2,5-dienoic acid and ssDNA

4IQV の概要

• エントリーDOI: 10.2210/pdb4iqv/pdb
• 関連するPDBエントリー: 4IQT 4IQU 4IQW
• 分子名称: DNA nucleotidylexotransferase, 5'-D(*GP*CP*CP*G)-3', SODIUM ION, ... (5 entities in total)
• 機能のキーワード: terminal transferase, transferase-transferase inhibitor-dna complex, transferase/transferase inhibitor/dna
• 由来する生物種: Mus musculus (mouse); 詳細
• 細胞内の位置: Isoform TDT-S: Nucleus. Isoform TDT-L: Cytoplasm. Nucleus : P09838
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 47206.03

構造登録者

Gouge, J.,Delarue, M. (登録日: 2013-01-13, 公開日: 2013-09-04, 最終更新日: 2023-09-20)

主引用文献

Costi, R.,Cuzzucoli Crucitti, G.,Pescatori, L.,Messore, A.,Scipione, L.,Tortorella, S.,Amoroso, A.,Crespan, E.,Campiglia, P.,Maresca, B.,Porta, A.,Granata, I.,Novellino, E.,Gouge, J.,Delarue, M.,Maga, G.,Di Santo, R.
New nucleotide-competitive non-nucleoside inhibitors of terminal deoxynucleotidyl transferase: discovery, characterization, and crystal structure in complex with the target.
J.Med.Chem., 56:7431-7441, 2013

PubMed Abstract: Terminal deoxynucletidyl transferase (TdT) is overexpressed in some cancer types, where it might compete with pol μ during the mutagenic repair of double strand breaks (DSBs) through the nonhomologous end joining (NHEJ) pathway. Here we report the discovery and characterization of pyrrolyl and indolyl diketo acids that specifically target TdT and behave as nucleotide-competitive inhibitors. These compounds show a selective toxicity toward MOLT-4 compared to HeLa cells that correlate well with in vitro selectivity for TdT. The binding site of two of these inhibitors was determined by cocrystallization with TdT, explaining why these compounds are competitive inhibitors of the deoxynucleotide triphosphate (dNTP). In addition, because of the observed dual localization of the phenyl substituent, these studies open the possibility of rationally designing more potent compounds.

PubMed: 23968551
DOI: 10.1021/jm4010187

実験手法

X-RAY DIFFRACTION (2.9 Å)