4IQT

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

Summary for 4IQT

• Entry DOI: 10.2210/pdb4iqt/pdb
• Related: 4IQU 4IQV 4IQW
• Descriptor: DNA nucleotidylexotransferase, 6-[4-(3-fluorobenzoyl)-1H-pyrrol-2-yl]-2-hydroxy-4-oxohexa-2,5-dienoic acid (3 entities in total)
• Functional Keywords: terminal transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Mus musculus (mouse); More
• Cellular location: Isoform TDT-S: Nucleus. Isoform TDT-L: Cytoplasm. Nucleus : P09838
• Total number of polymer chains: 1
• Total formula weight: 46033.30

Authors

Gouge, J.,Delarue, M. (deposition date: 2013-01-13, release date: 2013-09-04, Last modification date: 2023-09-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.6 Å)