TY - JOUR TI - Structures of ferroportin in complex with its specific inhibitor vamifeport AU - Lehmann, Elena Farah AU - Liziczai, Márton AU - Drożdżyk, Katarzyna AU - Altermatt, Patrick AU - Langini, Cassiano AU - Manolova, Vania AU - Sundstrom, Hanna AU - Dürrenberger, Franz AU - Dutzler, Raimund AU - Manatschal, Cristina A2 - Maduke, Merritt A2 - Aldrich, Richard W A2 - Gaudet, Rachelle VL - 12 PY - 2023 DA - 2023/03/21 SP - e83053 C1 - eLife 2023;12:e83053 DO - 10.7554/eLife.83053 UR - https://doi.org/10.7554/eLife.83053 AB - A central regulatory mechanism of iron homeostasis in humans involves ferroportin (FPN), the sole cellular iron exporter, and the peptide hormone hepcidin, which inhibits Fe2+ transport and induces internalization and degradation of FPN. Dysregulation of the FPN/hepcidin axis leads to diverse pathological conditions, and consequently, pharmacological compounds that inhibit FPN-mediated iron transport are of high clinical interest. Here, we describe the cryo-electron microscopy structures of human FPN in complex with synthetic nanobodies and vamifeport (VIT-2763), the first clinical-stage oral FPN inhibitor. Vamifeport competes with hepcidin for FPN binding and is currently in clinical development for β-thalassemia and sickle cell disease. The structures display two distinct conformations of FPN, representing outward-facing and occluded states of the transporter. The vamifeport site is located in the center of the protein, where the overlap with hepcidin interactions underlies the competitive relationship between the two molecules. The introduction of point mutations in the binding pocket of vamifeport reduces its affinity to FPN, emphasizing the relevance of the structural data. Together, our study reveals conformational rearrangements of FPN that are of potential relevance for transport, and it provides initial insight into the pharmacological targeting of this unique iron efflux transporter. KW - cryo-electron microscopy KW - iron transport protein KW - pharmacology JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -