7u4k
From Proteopedia
Crystal structure of human GPX4-U46C-R152H in complex with ML162
Structural highlights
FunctionGPX4_HUMAN Protects cells against membrane lipid peroxidation and cell death. Required for normal sperm development and male fertility. Could play a major role in protecting mammals from the toxicity of ingested lipid hydroperoxides. Essential for embryonic development. Protects from radiation and oxidative damage (By similarity). Publication Abstract from PubMedEncouraged 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. Small-molecule allosteric inhibitors of GPX4.,Liu H, Forouhar F, Lin AJ, Wang Q, Polychronidou V, Soni RK, Xia X, Stockwell BR Cell Chem Biol. 2022 Dec 15;29(12):1680-1693.e9. doi: , 10.1016/j.chembiol.2022.11.003. Epub 2022 Nov 23. PMID:36423641[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Homo sapiens | Large Structures | Forouhar F | Lin AJ | Liu H | Soni RK | Stockwell BR | Wang Q | Xia X
