8BZY
Structure of SLC40/ferroportin in complex with vamifeport and synthetic nanobody Sy3 in occluded conformation
Summary for 8BZY
| Entry DOI | 10.2210/pdb8bzy/pdb |
| EMDB information | 16345 |
| Descriptor | Solute carrier family 40 member 1, Sybody 3, DIUNDECYL PHOSPHATIDYL CHOLINE, ... (4 entities in total) |
| Functional Keywords | iron, inhibitor, slc40, transporter, transport protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 80911.21 |
| Authors | Lehmann, E.F.,Liziczai, M.,Drozdzyk, K.,Dutzler, R.,Manatschal, C. (deposition date: 2022-12-15, release date: 2023-03-22, Last modification date: 2024-10-16) |
| Primary citation | Lehmann, E.F.,Liziczai, M.,Drozdzyk, K.,Altermatt, P.,Langini, C.,Manolova, V.,Sundstrom, H.,Durrenberger, F.,Dutzler, R.,Manatschal, C. Structures of ferroportin in complex with its specific inhibitor vamifeport. Elife, 12:-, 2023 Cited by PubMed Abstract: A central regulatory mechanism of iron homeostasis in humans involves ferroportin (FPN), the sole cellular iron exporter, and the peptide hormone hepcidin, which inhibits Fe 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. PubMed: 36943194DOI: 10.7554/eLife.83053 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.24 Å) |
Structure validation
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