7U4N
Crystal structure of human GPX4-U46C in complex with RSL3
Summary for 7U4N
| Entry DOI | 10.2210/pdb7u4n/pdb |
| Descriptor | Phospholipid hydroperoxide glutathione peroxidase, methyl (1S,3R)-2-(chloroacetyl)-1-[4-(methoxycarbonyl)phenyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate (3 entities in total) |
| Functional Keywords | gpx4, oxidoreductase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 44657.95 |
| Authors | Forouhar, F.,Liu, H.,Lin, A.J.,Wang, Q.,Xia, X.,Soni, R.K.,Stockwell, B.R. (deposition date: 2022-02-28, release date: 2022-12-07, Last modification date: 2024-10-09) |
| Primary citation | 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 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: 36423641DOI: 10.1016/j.chembiol.2022.11.003 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.6 Å) |
Structure validation
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