6MK3

Crystallographic solvent mapping analysis of DMSO bound to APE1

6MK3 の概要

• エントリーDOI: 10.2210/pdb6mk3/pdb
• 分子名称: DNA-(apurinic or apyrimidinic site) lyase, DIMETHYL SULFOXIDE, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: apurinic/apyrimidinic endonuclease, dna repair, abasic site, solvent mapping, lyase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32353.85

構造登録者

Georgiadis, M.M.,He, H.,Chen, Q. (登録日: 2018-09-24, 公開日: 2019-01-30, 最終更新日: 2024-03-13)

主引用文献

Trilles, R.,Beglov, D.,Chen, Q.,He, H.,Wireman, R.,Reed, A.,Chennamadhavuni, S.,Panek, J.S.,Brown, L.E.,Vajda, S.,Porco Jr., J.A.,Kelley, M.R.,Georgiadis, M.M.
Discovery of Macrocyclic Inhibitors of Apurinic/Apyrimidinic Endonuclease 1.
J. Med. Chem., 62:1971-1988, 2019

PubMed Abstract: Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential base excision repair enzyme that is upregulated in a number of cancers, contributes to resistance of tumors treated with DNA-alkylating or -oxidizing agents, and has recently been identified as an important therapeutic target. In this work, we identified hot spots for binding of small organic molecules experimentally in high resolution crystal structures of APE1 and computationally through the use of FTMAP analysis ( http://ftmap.bu.edu/ ). Guided by these hot spots, a library of drug-like macrocycles was docked and then screened for inhibition of APE1 endonuclease activity. In an iterative process, hot-spot-guided docking, characterization of inhibition of APE1 endonuclease, and cytotoxicity of cancer cells were used to design next generation macrocycles. To assess target selectivity in cells, selected macrocycles were analyzed for modulation of DNA damage. Taken together, our studies suggest that macrocycles represent a promising class of compounds for inhibition of APE1 in cancer cells.

PubMed: 30653918
DOI: 10.1021/acs.jmedchem.8b01529

実験手法

X-RAY DIFFRACTION (1.478 Å)