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7U4J

Crystal structure of human GPX4-U46C-R152H in complex with TMT10

Summary for 7U4J
Entry DOI10.2210/pdb7u4j/pdb
DescriptorPhospholipid hydroperoxide glutathione peroxidase, ~{N}-(3-chloranyl-4-methoxy-phenyl)ethanamide, THIOCYANATE ION, ... (4 entities in total)
Functional Keywordsgpx4, oxidoreductase
Biological sourceHomo sapiens (human)
Total number of polymer chains1
Total formula weight22126.77
Authors
Forouhar, F.,Liu, H.,Lin, A.J.,Wang, Q.,Polychronidou, V.,Soni, R.K.,Xia, X.,Stockwell, B.R. (deposition date: 2022-02-28, release date: 2022-12-07, Last modification date: 2024-11-13)
Primary citationLiu, 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
Cited by
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
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.81 Å)
Structure validation

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