7ZUS

Crystal structure of ternary complex of Pol theta polymerase domain

これはPDB形式変換不可エントリーです。

7ZUS の概要

• エントリーDOI: 10.2210/pdb7zus/pdb
• 分子名称: DNA polymerase theta, DNA (5'-D(P*TP*TP*CP*CP*AP*AP*TP*GP*AP*CP*AP*GP*CP*CP*GP*C)-3'), DNA (5'-D(*GP*CP*GP*GP*CP*TP*GP*TP*CP*AP*TP*TP*(DDG))-3'), ... (6 entities in total)
• 機能のキーワード: dna polymerase, protein-dna complex, dna repair, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 9
• 化学式量合計: 273338.87

構造登録者

Krajewski, W.W.,Turnbull, A.P.,Willis, S.,Charles, M.,Stockley, M.,Heald, R.A. (登録日: 2022-05-13, 公開日: 2022-10-12, 最終更新日: 2024-01-31)

主引用文献

Stockley, M.L.,Ferdinand, A.,Benedetti, G.,Blencowe, P.,Boyd, S.M.,Calder, M.,Charles, M.D.,Edwardes, L.V.,Ekwuru, T.,Finch, H.,Galbiati, A.,Geo, L.,Grande, D.,Grinkevich, V.,Holliday, N.D.,Krajewski, W.W.,MacDonald, E.,Majithiya, J.B.,McCarron, H.,McWhirter, C.L.,Patel, V.,Pedder, C.,Rajendra, E.,Ranzani, M.,Rigoreau, L.J.M.,Robinson, H.M.R.,Schaedler, T.,Sirina, J.,Smith, G.C.M.,Swarbrick, M.E.,Turnbull, A.P.,Willis, S.,Heald, R.A.
Discovery, Characterization, and Structure-Based Optimization of Small-Molecule In Vitro and In Vivo Probes for Human DNA Polymerase Theta.
J.Med.Chem., 65:13879-13891, 2022

PubMed Abstract: Human DNA polymerase theta (Polθ), which is essential for microhomology-mediated DNA double strand break repair, has been proposed as an attractive target for the treatment of BRCA deficient and other DNA repair pathway defective cancers. As previously reported, we recently identified the first selective small molecule Polθ in vitro probe, (ART558), which recapitulates the phenotype of Polθ loss, and in vivo probe, (ART812), which is efficacious in a model of PARP inhibitor resistant TNBC in vivo. Here we describe the discovery, biochemical and biophysical characterization of these probes including small molecule ligand co-crystal structures with Polθ. The crystallographic data provides a basis for understanding the unique mechanism of inhibition of these compounds which is dependent on stabilization of a "closed" enzyme conformation. Additionally, the structural biology platform provided a basis for rational optimization based primarily on reduced ligand conformational flexibility.

PubMed: 36200480
DOI: 10.1021/acs.jmedchem.2c01142

実験手法

X-RAY DIFFRACTION (2.26 Å)