Structures of ferroportin in complex with its specific inhibitor vamifeport

The regulation of iron balance in humans is centrally controlled by ferroportin (FPN), the only cellular iron exporter, and the peptide hormone hepcidin, which blocks Fe2+ transport by promoting the internalization and degradation of FPN. Disruption of the FPN/hepcidin axis is linked to various diseases, making inhibitors of FPN-mediated iron transport clinically significant. In this study, we present the cryo-electron microscopy structures of human FPN in complex with synthetic nanobodies and vamifeport (VIT-2763), the first oral FPN inhibitor to reach clinical trials. Vamifeport competes with hepcidin for binding to FPN and is currently being developed for the treatment of β-thalassemia and sickle cell disease. The structures reveal two distinct conformations of FPN, corresponding to outward-facing and occluded states of the transporter. Vamifeport binds at a central site within the protein, where it overlaps with hepcidin’s interaction site, highlighting their competitive binding. Point mutations in vamifeport’s binding pocket reduce its affinity for FPN, underscoring the importance of the structural insights provided. Overall, this study uncovers conformational changes in FPN that may influence its transport function and offers valuable information for the pharmacological targeting of this unique iron efflux transporter.