Structural basis of ferroportin inhibition by minihepcidin PR73

• DOI: 10.1371/journal.pbio.3001936
• Publication Date: 2023-01-18T04:05:23Z
• Authors: Azaan Saalim Wilbon; Jiemin Shen; Piotr Ruchala; Ming Zhou; Yaping Pan
• Keywords: Ferroportin; Hereditary hemochromatosis

Ferroportin (Fpn) is the only known iron exporter in humans and essential for maintaining homeostasis. Fpn activity suppressed by hepcidin, an endogenous peptide hormone, which inhibits export promotes endocytosis of Fpn. Hepcidin deficiency leads to hemochromatosis iron-loading anemia. Previous studies have shown that small peptides mimic first few residues i.e., minihepcidins, are more potent than hepcidin. However, mechanism enhanced inhibition minihepcidins remains unclear. Here, we report structure human ferroportin complex with a minihepcidin, PR73 mimics 9 at 2.7 Å overall resolution. The reveals novel interactions were not present between We validate PR73-Fpn through binding transport assays. These results provide insights into how increase potency will guide future development inhibitors.