5x5p
Human serum transferrin bound to ruthenium NTA
Structural highlights
DiseaseTRFE_HUMAN Defects in TF are the cause of atransferrinemia (ATRAF) [MIM:209300. Atransferrinemia is rare autosomal recessive disorder characterized by iron overload and hypochromic anemia.[1] [2] FunctionTRFE_HUMAN Transferrins are iron binding transport proteins which can bind two Fe(3+) ions in association with the binding of an anion, usually bicarbonate. It is responsible for the transport of iron from sites of absorption and heme degradation to those of storage and utilization. Serum transferrin may also have a further role in stimulating cell proliferation. Publication Abstract from PubMedBeing identified with less toxic and generally showing selective effects for solid tumor metastases, ruthenium and osmium compounds are promising drug candidates for clinical uses. Human serum proteins, such as albumin and transferrin, play vital roles in the transportation and accumulation of ruthenium and osmium agents into target tissues. However, the molecular mechanism of how transferrin transport ruthenium and their osmium analogues at atomic level remains obscure. In this study, we uncovered that the cellular uptake of Os(3+) or Ru(3+) are not competed by Fe(3+). To unveil the molecular mechanism behind the phenomena, we report the first crystal structures of human serum transferrin (hTF) in complex with ruthenium and osmium compounds bound to the non-conserved residues on the surface of hTF without altering its overall conformation. As for Ru(3+) and Os(3+), these binding sites by descending affinity are: His14/His289, His349-350 ~ His578/Arg581. Ruthenium drugs and their osmium analogues preferentially bind to His14/His289 with bipyridine or imidazole ligands leaving. These binding sites on hTF surface are also available in human lactoferrin and some transferrin family member of other species. The presence of these binding sites makes the cellular uptake of Ru(3+) and Os(3+) less affected by Fe(3+), compare to Zr(4+) or Hf(4+). Collectively, these findings are critical for our understanding of the role of serum transferrin in cellular delivery of ruthenium and osmium anticancer agents. Binding of ruthenium and osmium at nonâiron sites of transferrin accounts for their iron-independent cellular uptake.,Wang M, Wang H, Xu X, Lai TP, Zhou Y, Hao Q, Li H, Sun H J Inorg Biochem. 2022 Sep;234:111885. doi: 10.1016/j.jinorgbio.2022.111885. Epub , 2022 Jun 2. PMID:35690040[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
