9DEX
Crystal structure of human peroxiredoxin 1 in complex with inhibitor WF-097
Summary for 9DEX
| Entry DOI | 10.2210/pdb9dex/pdb |
| Descriptor | Peroxiredoxin-1, 1,2-ETHANEDIOL, SULFATE ION, ... (6 entities in total) |
| Functional Keywords | human peroxiredoxin 1, oxidoreductase, covalent inhibitor complex |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 45931.95 |
| Authors | Lowther, W.T.,Gumpena, R. (deposition date: 2024-08-29, release date: 2025-10-29, Last modification date: 2025-11-19) |
| Primary citation | Nelson, K.J.,Smalley Jr., T.L.,Messier, T.,Gumpena, R.,Gandhi, U.,Milczarek, S.,Habibovic, A.,Hoffman, H.,Gibson, V.,Hondal, R.J.,Lowther, W.T.,Cunniff, B. Mechanism-based peroxiredoxin 3 inhibitors exploit a covalent warhead for cancer therapy. Sci Adv, 11:eady4492-eady4492, 2025 Cited by PubMed Abstract: Covalent inhibitors that are approved and marketed drugs exploit a wide array of warheads and reactions with amino acid side chain-based nucleophiles. Thiostrepton (TS) inhibits the peroxidase activity of the mitochondrial antioxidant protein peroxiredoxin 3 by forming a covalent crosslink between the two active site cysteine residues. Peroxiredoxin 3 inactivation increases reactive oxygen species levels, induces cancer cell death in preclinical models, and shows promise in an ongoing clinical trial for malignant mesothelioma using direct pleural infusion. We report the identification of the minimal fragment of TS that contains tandem dehydro-alanine (DHA) moieties and maintains anticancer activity while losing interactions with three alternative targets of intact TS. Biochemical, kinetic, cellular, and structural studies demonstrate that this fragment is a mechanism-based peroxiredoxin inhibitor. These findings represent a promising start toward a pro-oxidant approach for cancer therapy. Moreover, the data support that the DHA moiety should be added to the covalent warhead arsenal. PubMed: 41171914DOI: 10.1126/sciadv.ady4492 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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