7U4L

Crystal structure of human GPX4-U46C in complex with MAC-5576

7U4L の概要

• エントリーDOI: 10.2210/pdb7u4l/pdb
• 分子名称: Phospholipid hydroperoxide glutathione peroxidase, thiophene-2-carbaldehyde (3 entities in total)
• 機能のキーワード: gpx4, oxidoreductase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 88449.59

構造登録者

Forouhar, F.,Liu, H.,Lin, A.J.,Wang, Q.,Polychronidou, V.,Soni, R.K.,Xia, X.,Stockwell, B.R. (登録日: 2022-02-28, 公開日: 2022-12-07, 最終更新日: 2024-10-23)

主引用文献

Liu, H.,Forouhar, F.,Lin, A.J.,Wang, Q.,Polychronidou, V.,Soni, R.K.,Xia, X.,Stockwell, B.R.
Small-molecule allosteric inhibitors of GPX4.
Cell Chem Biol, 29:1680-1693.e9, 2022

PubMed Abstract: Encouraged by the dependence of drug-resistant, metastatic cancers on GPX4, we examined biophysical mechanisms of GPX4 inhibition, which revealed an unexpected allosteric site. We found that this site was involved in native regeneration of GPX4 under low glutathione conditions. Covalent binding of inhibitors to this allosteric site caused a conformational change, inhibition of activity, and subsequent cellular GPX4 protein degradation. To verify this site in an unbiased manner, we screened a library of compounds and identified and validated that an additional compound can covalently bind in this allosteric site, inhibiting and degrading GPX4. We determined co-crystal structures of six different inhibitors bound in this site. We have thus identified an allosteric mechanism for small molecules targeting aggressive cancers dependent on GPX4.

PubMed: 36423641
DOI: 10.1016/j.chembiol.2022.11.003

実験手法

X-RAY DIFFRACTION (2.25 Å)