6DJJ

Crystal structure of Tdp1 catalytic domain in complex with compound XZ532

Summary for 6DJJ

• Entry DOI: 10.2210/pdb6djj/pdb
• Descriptor: Tyrosyl-DNA phosphodiesterase 1, 4-aminobenzene-1,2-dicarboxylic acid, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: fragment-based drug design, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 105049.44

Authors

Lountos, G.T.,Zhao, X.Z.,Kiselev, E.,Tropea, J.E.,Needle, D.,Burke Jr., T.R.,Pommier, Y.,Waugh, D.S. (deposition date: 2018-05-25, release date: 2019-05-29, Last modification date: 2023-10-11)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.741 Å)