Cisplatin/Apo-Transferrin\nAdduct: X‑ray Structure\nand Binding to the Transferrin Receptor 1

Here, we report the X-ray structure of the adduct formed\nupon reaction\nof cisplatin, one of the most prescribed anticancer agents for the\nclinic treatment of solid tumors, with the apo-form of human serum\ntransferrin (hTF). Two Pt binding sites were identified in both molecules\nof the adduct present in the crystal asymmetric unit: Pt binds close\nto the side chains of Met256 and Met499 at the N- and C-lobe, respectively.\nIn the crystal structure, the cisplatin moiety bound to Met256 also\ninteracts with Ser616 from a symmetry related molecule. Structural\nanalyses, together with in solution data, demonstrate that the presence\nof iron does not affect the ability of hTF to bind cisplatin and that\nthe cisplatin binding does not significantly alter the overall conformation\nof the different forms of the protein that remain able to form a complex\nwith the transferrin receptor 1 (TfR1). These data suggest that the\ndifferent hTF forms can be used as nanocarriers for targeted (combined)\nmetallodrug delivery.