Structural characterization of vanadium binding to human serum transferrin

Human serum transferrin (hTF), the major iron-transport protein in blood, can also interact with non-Fe ions and with metal compounds of medicinal interest, potentially influencing their distribution and biological activity.¹ Vanadium compounds have attracted considerable interest for their pharmacological properties, although the molecular consequences of their interaction with hTF are not fully understood.² Recently, crystallographic studies provided the first evidence at atomic level of vanadium binding to a monoferric form of hTF.³

Here, the interaction between the apo form of hTF and the potential metallodrug [V^IVO(acac)₂] was investigated by X-ray crystallography and urea-polyacrylamide gel electrophoresis (Urea-PAGE). Crystals obtained by co-crystallization after 24 and 48 h of incubation revealed the formation of divanadate(V) species. Two [V^V₂O₆]²⁻ anions were identified within the Fe³⁺ binding sites coordinated to Tyr188 and Tyr517, respectively. Notably, vanadium binding to Tyr517 had not been previously reported.

Despite occupation of the Fe³⁺-binding sites, structural analysis showed that hTF retains the NopenCopen conformation characteristic of its apo form, indicating that divanadate(V) binding does not induce the conformational rearrangements typically associated with Fe³⁺ binding. Urea-PAGE experiments confirmed that this occurs also in solution.

Thus, hTF binds divanadate(V) species within iron-binding sites without undergoing the conformational transition associated with efficient transferrin receptor recognition. These findings provide molecular insights into vanadium–transferrin interactions and support a limited contribution of vanadium(V)-bound hTF to cellular vanadium uptake through receptor-mediated endocytosis.

References

1. Silva AMN et al. Coord Chem Rev. 2021;449:214186.

2. Correia I et al. Chem Asian J. 2017;12:2062–2084.

3. Banneville AS et al. Commun Chem. 2026;9:89.