8c02
Structure of SLC40/ferroportin in complex with synthetic nanobody Sy3 in occluded conformation
Structural highlights
DiseaseS40A1_HUMAN SLC40A1-related hemochromatosis;Ferroportin disease. The disease is caused by variants affecting the gene represented in this entry. FunctionS40A1_HUMAN Transports Fe(2+) from the inside of a cell to the outside of the cell, playing a key role for maintaining systemic iron homeostasis (PubMed:15692071, PubMed:22178646, PubMed:22682227, PubMed:24304836, PubMed:29237594, PubMed:29599243, PubMed:30247984). Transports iron from intestinal, splenic, hepatic cells, macrophages and erythrocytes into the blood to provide iron to other tissues (By similarity). Controls therefore dietary iron uptake, iron recycling by macrophages and erythrocytes, and release of iron stores in hepatocytes (By similarity). When iron is in excess in serum, circulating HAMP/hepcidin levels increase resulting in a degradation of SLC40A1, thus limiting the iron efflux to plasma (PubMed:22682227, PubMed:29237594, PubMed:32814342).[UniProtKB:Q9JHI9][1] [2] [3] [4] [5] [6] [7] [8] Publication Abstract from PubMedA central regulatory mechanism of iron homeostasis in humans involves ferroportin (FPN), the sole cellular iron exporter, and the peptide hormone hepcidin, which inhibits Fe(2+) 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 beta-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. Structures of ferroportin in complex with its specific inhibitor vamifeport.,Lehmann EF, Liziczai M, Drozdzyk K, Altermatt P, Langini C, Manolova V, Sundstrom H, Durrenberger F, Dutzler R, Manatschal C Elife. 2023 Mar 21;12:e83053. doi: 10.7554/eLife.83053. PMID:36943194[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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