First crystal structure of an adduct formed upon reaction of a vanadium compound with human serum transferrin

The interaction of vanadium compounds of pharmaceutical interest with metal-transport proteins like human serum transferrin (hTF) is poorly understood. Direct structural evidence identifying vanadium binding sites on hTF is still lacking. Here, the X-ray structure of the adduct formed when the potential drug [VIVO(acac)2], with acac = acetylacetonato, reacts with human serum transferrin with Fe3+ bound at the C-lobe only (FeC-hTF) has been solved and compared with new structures of FeC-hTF used as controls. Structural analysis revealed the presence of a [VV2O6]2– anion that can be described as a divanadate(V) anion, [VV2O7]4–, that has one oxygen replaced by the phenolate oxygen of Tyr188. The two vanadium centers adopt tetrahedral geometry, consistent with VV behavior. The binding does not alter the overall conformation of FeC-hTF that retains the open conformation of the N-lobe and the closed conformation of the C-lobe, remaining able to be recognized by the transferrin receptor. Human serum transferrin plays a crucial role in iron homeostasis, but its interaction with potential metallodrugs remains underexplored. Here, the authors solve the X-ray structure of an adduct between transferrin (FeC-hTF) and [VV2O6]2–, generated from a vanadium-based drug [VIVO(acac)2], showing that binding preserves the overall conformation of FeC-hTF.