8TVT
Structure of human Cysteine desulfurase Nfs1 with L-propargylglycine bound to active site PLP in complex with ISD11, Acp1 and ISCU2
Summary for 8TVT
| Entry DOI | 10.2210/pdb8tvt/pdb |
| Descriptor | Cysteine desulfurase, TETRAETHYLENE GLYCOL, 2,5,8,11,14,17-HEXAOXANONADECAN-19-OL, ... (18 entities in total) |
| Functional Keywords | nfs1, pg-plp bound, transferase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 84137.02 |
| Authors | Cygler, M.,Boniecki, M.T. (deposition date: 2023-08-18, release date: 2024-09-11, Last modification date: 2025-08-27) |
| Primary citation | Zangari, J.,Stehling, O.,Freibert, S.A.,Bhattacharya, K.,Rouaud, F.,Serre-Beinier, V.,Maundrell, K.,Montessuit, S.,Ferre, S.M.,Vartholomaiou, E.,Schulz, V.,Zuhra, K.,Gonzalez-Ruiz, V.,Hanschke, S.,Tsukamoto, T.,Cerezo, M.,Szabo, C.,Rudaz, S.,Boniecki, M.T.,Cygler, M.,Lill, R.,Martinou, J.C. D-cysteine impairs tumour growth by inhibiting cysteine desulfurase NFS1. Nat Metab, 2025 Cited by PubMed Abstract: Selective targeting of cancer cells is a major challenge for cancer therapy. Many cancer cells overexpress the cystine/glutamate antiporter xCT/CD98, an L-cystine transport system that strengthens antioxidant defences, thereby promoting tumour survival and progression. Here, we show that the D-enantiomer of cysteine (D-Cys) is selectively imported into xCT/CD98-overexpressing cancer cell lines and impairs their proliferation, particularly under high oxygen concentrations. Intracellular D-Cys specifically inhibits the mitochondrial cysteine desulfurase NFS1, a key enzyme of cellular iron-sulfur protein biogenesis, by blocking sulfur mobilization due to steric constraints. NFS1 inhibition by D-Cys affects all cellular iron-sulfur cluster-dependent functions, including mitochondrial respiration, nucleotide metabolism and maintenance of genome integrity, leading to decreased oxygen consumption, DNA damage and cell cycle arrest. D-Cys administration diminishes tumour growth of human triple-negative breast cancer cells implanted orthotopically into the mouse mammary gland. Hence, D-Cys could represent a simple therapy to selectively target those forms of cancer characterized by overexpression of xCT/CD98. PubMed: 40797101DOI: 10.1038/s42255-025-01339-1 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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