8CVQ

Crystal structure of TDP1 complexed with compound XZ761

8CVQ の概要

• エントリーDOI: 10.2210/pdb8cvq/pdb
• 分子名称: Tyrosyl-DNA phosphodiesterase 1, 4-{[(4S)-2,7-diphenylimidazo[1,2-a]pyridin-3-yl]amino}benzene-1,2-dicarboxylic acid, 3[N-MORPHOLINO]PROPANE SULFONIC ACID, ... (5 entities in total)
• 機能のキーワード: phosphodiesterase, 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: 106004.59

構造登録者

Lountos, G.T.,Zhao, X.Z.,Wang, W.,Kiselev, E.,Tropea, J.E.,Needle, D.,Pommier, Y.,Burke, T.R. (登録日: 2022-05-18, 公開日: 2023-04-12, 最終更新日: 2023-10-25)

主引用文献

Zhao, X.Z.,Wang, W.,Lountos, G.T.,Kiselev, E.,Tropea, J.E.,Needle, D.,Pommier, Y.,Burke Jr., T.R.
Identification of multidentate tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors that simultaneously access the DNA, protein and catalytic-binding sites by oxime diversification.
Rsc Chem Biol, 4:334-343, 2023

PubMed Abstract: Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a member of the phospholipase D family that can downregulate the anticancer effects of the type I topoisomerase (TOP1) inhibitors by hydrolyzing the 3'-phosphodiester bond between DNA and the TOP1 residue Y723 in the critical stalled intermediate that is the foundation of TOP1 inhibitor mechanism of action. Thus, TDP1 antagonists are attractive as potential enhancers of TOP1 inhibitors. However, the open and extended nature of the TOP1-DNA substrate-binding region has made the development of TDP1 inhibitors extremely challenging. In this study, starting from our recently identified small molecule microarray (SMM)-derived TDP1-inhibitory imidazopyridine motif, we employed a click-based oxime protocol to extend the parent platform into the DNA and TOP1 peptide substrate-binding channels. We applied one-pot Groebke-Blackburn-Bienayme multicomponent reactions (GBBRs) to prepare the needed aminooxy-containing substrates. By reacting these precursors with approximately 250 aldehydes in microtiter format, we screened a library of nearly 500 oximes for their TDP1 inhibitory potencies using an florescence-based catalytic assay. Select hits were structurally explored as their triazole- and ether-based isosteres. We obtained crystal structures of two of the resulting inhibitors bound to the TDP1 catalytic domain. The structures reveal that the inhibitors form hydrogen bonds with the catalytic His-Lys-Asn triads ("HKN" motifs: H263, K265, N283 and H493, K495, N516), while simultaneously extending into both the substrate DNA and TOP1 peptide-binding grooves. This work provides a structural model for developing multivalent TDP1 inhibitors capable of binding in a tridentate fashion with a central component situated within the catalytic pocket and extensions that project into both the DNA and TOP1 peptide substrate-binding regions.

PubMed: 37181631
DOI: 10.1039/d2cb00230b

実験手法

X-RAY DIFFRACTION (1.65 Å)