8c03

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[8c03]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8C03 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8C03 FirstGlance]. <br>
<table><tr><td colspan='2'>[[8c03]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8C03 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8C03 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SZU:2-[2-[2-(1~{H}-benzimidazol-2-yl)ethylamino]ethyl]-~{N}-[(3-fluoranylpyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide'>SZU</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.89&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SZU:2-[2-[2-(1~{H}-benzimidazol-2-yl)ethylamino]ethyl]-~{N}-[(3-fluoranylpyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide'>SZU</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8c03 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8c03 OCA], [https://pdbe.org/8c03 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8c03 RCSB], [https://www.ebi.ac.uk/pdbsum/8c03 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8c03 ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8c03 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8c03 OCA], [https://pdbe.org/8c03 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8c03 RCSB], [https://www.ebi.ac.uk/pdbsum/8c03 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8c03 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
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[https://www.uniprot.org/uniprot/S40A1_HUMAN S40A1_HUMAN] Hemochromatosis type 4. The disease is caused by variants affecting the gene represented in this entry.
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[https://www.uniprot.org/uniprot/S40A1_HUMAN S40A1_HUMAN] SLC40A1-related hemochromatosis;Ferroportin disease. The disease is caused by variants affecting the gene represented in this entry.
== Function ==
== Function ==
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[https://www.uniprot.org/uniprot/S40A1_HUMAN S40A1_HUMAN] Major iron transporter that plays a key role in balancing cellular and systemic iron levels (PubMed:29237594, PubMed:22682227, PubMed:15692071). Transports iron from intestinal, splenic, and hepatic cells into the blood to provide iron to other tissues (By similarity). Controls therefore dietary iron uptake, iron recycling by macrophages, and release of iron stores in hepatocytes (By similarity). When iron is in excess, hepcidin/HAMP levels increase resulting in a degradation of ferroportin/SLC40A1 limiting the iron efflux to plasma (PubMed:22682227, PubMed:29237594, PubMed:32814342).[UniProtKB:Q9JHI9]<ref>PMID:15692071</ref> <ref>PMID:22682227</ref> <ref>PMID:29237594</ref> <ref>PMID:32814342</ref>
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[https://www.uniprot.org/uniprot/S40A1_HUMAN S40A1_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]<ref>PMID:15692071</ref> <ref>PMID:22178646</ref> <ref>PMID:22682227</ref> <ref>PMID:24304836</ref> <ref>PMID:29237594</ref> <ref>PMID:29599243</ref> <ref>PMID:30247984</ref> <ref>PMID:32814342</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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(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.
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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<ref>PMID:36943194</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 8c03" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>

Current revision

Structure of SLC40/ferroportin in complex with vamifeport and synthetic nanobody Sy12 in outward-facing conformation

PDB ID 8c03

Drag the structure with the mouse to rotate

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OCA

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