Department of Chemistry and CAS-HKU Joint Laboratory of Metallomics for Health and Environment, the University of Hong Kong, Pokfulam Road, Hong Kong SAR, China; School of Chemistry and Molecular Engineering, East China Normal University, No. 3663 Zhong Shan Road North, Shanghai 200062, China.
Department of Chemistry and CAS-HKU Joint Laboratory of Metallomics for Health and Environment, the University of Hong Kong, Pokfulam Road, Hong Kong SAR, China.
J Inorg Biochem. 2022 Sep;234:111885. doi: 10.1016/j.jinorgbio.2022.111885. Epub 2022 Jun 2.
Being 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 or Ru are not competed by Fe. 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 and Os, 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 and Os less affected by Fe, compare to Zr or Hf. Collectively, these findings are critical for our understanding of the role of serum transferrin in cellular delivery of ruthenium and osmium anticancer agents.
钌和锇化合物由于毒性较低且对实体瘤转移具有选择性，被认为是很有前途的临床应用药物候选物。人血清蛋白（如白蛋白和转铁蛋白）在将钌和锇化合物转运和积累到靶组织中起着至关重要的作用。然而，转铁蛋白如何以原子水平将钌和它们的锇类似物转运到靶组织的分子机制仍不清楚。在这项研究中，我们发现 Os 或 Ru 的细胞摄取不受 Fe 的竞争。为了揭示这一现象背后的分子机制，我们报告了人类血清转铁蛋白（hTF）与结合到 hTF 表面非保守残基上的钌和锇化合物复合物的首个晶体结构，而其整体构象并未改变。对于 Ru 和 Os，这些结合位点的亲和力依次为：His14/His289、His349-350~His578/Arg581。钌药物及其锇类似物优先与 His14/His289 结合，留下双吡啶或咪唑配体。hTF 表面上的这些结合位点也存在于人乳铁蛋白和其他物种的一些转铁蛋白家族成员中。这些结合位点的存在使得 Ru 和 Os 的细胞摄取受 Fe 的影响较小，与 Zr 或 Hf 相比。总的来说，这些发现对于我们理解血清转铁蛋白在细胞内递送钌和锇抗癌药物中的作用至关重要。
