6HKQ
Human GPX4 in complex with covalent Inhibitor ML162 (S enantiomer)
Summary for 6HKQ
| Entry DOI | 10.2210/pdb6hkq/pdb |
| Related | 6HN3 |
| Descriptor | Phospholipid hydroperoxide glutathione peroxidase, (2~{S})-2-[2-chloranylethanoyl-(3-chloranyl-4-methoxy-phenyl)amino]-~{N}-(2-phenylethyl)-2-thiophen-2-yl-ethanamide, SULFATE ION, ... (6 entities in total) |
| Functional Keywords | anti-oxidatve defense system, covalent inhibitor, oxidoreductase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 21158.03 |
| Authors | Hillig, R.C.,Moosmayer, D.,Hilpmann, A.,Hoffmann, L.,Schnirch, L.,Eaton, J.K.,Badock, V.,Gradl, S. (deposition date: 2018-09-07, release date: 2020-04-01, Last modification date: 2022-12-07) |
| Primary citation | Moosmayer, D.,Hilpmann, A.,Hoffmann, J.,Schnirch, L.,Zimmermann, K.,Badock, V.,Furst, L.,Eaton, J.K.,Viswanathan, V.S.,Schreiber, S.L.,Gradl, S.,Hillig, R.C. Crystal structures of the selenoprotein glutathione peroxidase 4 in its apo form and in complex with the covalently bound inhibitor ML162. Acta Crystallogr D Struct Biol, 77:237-248, 2021 Cited by PubMed Abstract: Wild-type human glutathione peroxidase 4 (GPX4) was co-expressed with SBP2 (selenocysteine insertion sequence-binding protein 2) in human HEK cells to achieve efficient production of this selenocysteine-containing enzyme on a preparative scale for structural biology. The protein was purified and crystallized, and the crystal structure of the wild-type form of GPX4 was determined at 1.0 Å resolution. The overall fold and the active site are conserved compared with previously determined crystal structures of mutated forms of GPX4. A mass-spectrometry-based approach was developed to monitor the reaction of the active-site selenocysteine Sec46 with covalent inhibitors. This, together with the introduction of a surface mutant (Cys66Ser), enabled the crystal structure determination of GPX4 in complex with the covalent inhibitor ML162 [(S)-enantiomer]. The mass-spectrometry-based approach described here opens the path to further co-complex crystal structures of this potential cancer drug target in complex with covalent inhibitors. PubMed: 33559612DOI: 10.1107/S2059798320016125 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.54 Å) |
Structure validation
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