7UFZ

Crystal structure of TDP1 complexed with compound XZ768

Summary for 7UFZ

• Entry DOI: 10.2210/pdb7ufz/pdb
• Descriptor: Tyrosyl-DNA phosphodiesterase 1, (4-{[(4S)-2-phenylimidazo[1,2-a]pyridin-3-yl]amino}phenyl)phosphonic acid, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: phosphodiesterase, dna binding protein, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 106226.57

Authors

Lountos, G.T.,Zhao, X.Z.,Wang, W.,Tropea, J.E.,Needle, D.,Pommier, Y.,Burke, T.R. (deposition date: 2022-03-23, release date: 2023-04-12, Last modification date: 2023-10-25)

Primary citation

Zhao, X.Z.,Wang, W.,Lountos, G.T.,Tropea, J.E.,Needle, D.,Pommier, Y.,Burke Jr., T.R.
Phosphonic acid-containing inhibitors of tyrosyl-DNA phosphodiesterase 1.
Front Chem, 10:910953-910953, 2022

PubMed Abstract: Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs stalled type I topoisomerase (TOP1)-DNA complexes by hydrolyzing the phosphodiester bond between the TOP1 Y723 residue and the 3'-phosphate of its DNA substrate. Although TDP1 antagonists could potentially reduce the dose of TOP1 inhibitors needed to achieve effective anticancer effects, the development of validated TDP1 inhibitors has proven to be challenging. This may, in part, be due to the open and extended nature of the TOP1 substrate binding region. We have previously reported imidazopyrazines and imidazopyridines that can inhibit TDP1 catalytic function . We solved the TDP1 crystal structures with bound inhibitors of this class and found that the dicarboxylic acid functionality within the -(3,4-dicarboxyphenyl)-2-diphenylimidazo []pyridin-3-amine platform overlaps with aspects of phosphoryl substrate recognition. Yet phosphonic acids could potentially better-replicate cognate TOP1-DNA substrate binding interactions than carboxylic acids. As reported herein, we designed phosphonic acid-containing variants of our previously reported carboxylic acid-containing imidazopyrazine and imidazopyridine inhibitors and effected their synthesis using one-pot Groebke-Blackburn-Bienayme multicomponent reactions. We obtained crystal structures of TDP1 complexed with a subset of inhibitors. We discuss binding interactions of these inhibitors within the context of phosphate-containing substrate and carboxylic acid-based inhibitors. These compounds represent a new structural class of small molecule ligands that mimic aspects of the 3'-processed substrate that results from TDP1 catalysis.

PubMed: 36051621
DOI: 10.3389/fchem.2022.910953

Experimental method

X-RAY DIFFRACTION (1.559 Å)