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- EMDB-16354: Structure of SLC40/ferroportin in complex with vamifeport and syn... -
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Open data
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Basic information
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Title | Structure of SLC40/ferroportin in complex with vamifeport and synthetic nanobody Sy12 in outward-facing conformation | |||||||||
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Function / homology | ![]() spleen trabecula formation / iron ion export across plasma membrane / Defective SLC40A1 causes hemochromatosis 4 (HFE4) (duodenum) / Defective SLC40A1 causes hemochromatosis 4 (HFE4) (macrophages) / Defective CP causes aceruloplasminemia (ACERULOP) / Metal ion SLC transporters / iron ion transmembrane transport / lymphocyte homeostasis / iron ion transmembrane transporter activity / ferrous iron transmembrane transporter activity ...spleen trabecula formation / iron ion export across plasma membrane / Defective SLC40A1 causes hemochromatosis 4 (HFE4) (duodenum) / Defective SLC40A1 causes hemochromatosis 4 (HFE4) (macrophages) / Defective CP causes aceruloplasminemia (ACERULOP) / Metal ion SLC transporters / iron ion transmembrane transport / lymphocyte homeostasis / iron ion transmembrane transporter activity / ferrous iron transmembrane transporter activity / endothelium development / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | |||||||||
Biological species | ![]() ![]() | |||||||||
Method | ![]() ![]() | |||||||||
![]() | Lehmann EF / Liziczai M / Drozdzyk K / Dutzler R / Manatschal C | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Structures of ferroportin in complex with its specific inhibitor vamifeport. Authors: Elena Farah Lehmann / Márton Liziczai / Katarzyna Drożdżyk / Patrick Altermatt / Cassiano Langini / Vania Manolova / Hanna Sundstrom / Franz Dürrenberger / Raimund Dutzler / Cristina Manatschal / ![]() 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 ...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. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 21 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 14.5 KB 14.5 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 8.3 KB | Display | ![]() |
Images | ![]() | 60.1 KB | ||
Masks | ![]() | 22.2 MB | ![]() | |
Others | ![]() ![]() | 20.7 MB 20.7 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8c03MC ![]() 8bzyC ![]() 8c02C M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.302 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
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Density Histograms |
-Half map: #1
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Density Histograms |
-Half map: #2
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Density Histograms |
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Sample components
-Entire : Complex of ferroportin with synthetic nanobody and inhibitor
Entire | Name: Complex of ferroportin with synthetic nanobody and inhibitor |
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Components |
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-Supramolecule #1: Complex of ferroportin with synthetic nanobody and inhibitor
Supramolecule | Name: Complex of ferroportin with synthetic nanobody and inhibitor type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1 Details: Ferroportin was expressed in human derived HEK cells, whereas the synthetic nanobody was expressed in bacterial cell culture. The two were purified separately and mixed shortly before vitrification |
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Source (natural) | Organism: ![]() ![]() |
-Macromolecule #1: Solute carrier family 40 member 1
Macromolecule | Name: Solute carrier family 40 member 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 63.536848 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MSTRAGDHNR QRGCCGSLAD YLTSAKFLLY LGHSLSTWGD RMWHFAVSVF LVELYGNSLL LTAVYGLVVA GSVLVLGAII GDWVDKNAR LKVAQTSLVV QNVSVILCGI ILMMVFLHKH ELLTMYHGWV LTSCYILIIT IANIANLAST ATAITIQRDW I VVVAGEDR ...String: MSTRAGDHNR QRGCCGSLAD YLTSAKFLLY LGHSLSTWGD RMWHFAVSVF LVELYGNSLL LTAVYGLVVA GSVLVLGAII GDWVDKNAR LKVAQTSLVV QNVSVILCGI ILMMVFLHKH ELLTMYHGWV LTSCYILIIT IANIANLAST ATAITIQRDW I VVVAGEDR SKLANMNATI RRIDQLTNIL APMAVGQIMT FGSPVIGCGF ISGWNLVSMC VEYVLLWKVY QKTPALAVKA GL KEEETEL KQLNLHKDTE PKPLEGTHLM GVKDSNIHEL EHEQEPTCAS QMAEPFRTFR DGWVSYYNQP VFLAGMGLAF LYM TVLGFD CITTGYAYTQ GLSGSILSIL MGASAITGIM GTVAFTWLRR KCGLVRTGLI SGLAQLSCLI LCVISVFMPG SPLD LSVSP FEDIRSRFIQ GESITPTKIP EITTEIYMSN GSNSANIVPE TSPESVPIIS VSLLFAGVIA ARIGLWSFDL TVTQL LQEN VIESERGIIN GVQNSMNYLL DLLHFIMVIL APNPEAFGLL VLISVSFVAM GHIMYFRFAQ NTLGNKLFAC GPDAKE VRK ENQANTSVVA LEVLFQG |
-Macromolecule #2: 2-[2-[2-(1~{H}-benzimidazol-2-yl)ethylamino]ethyl]-~{N}-[(3-fluor...
Macromolecule | Name: 2-[2-[2-(1~{H}-benzimidazol-2-yl)ethylamino]ethyl]-~{N}-[(3-fluoranylpyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide type: ligand / ID: 2 / Number of copies: 1 / Formula: SZU |
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Molecular weight | Theoretical: 408.429 Da |
Chemical component information | ![]() ChemComp-SZU: |
-Experimental details
-Structure determination
Method | ![]() |
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Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE-PROPANE / Chamber humidity: 100 % / Chamber temperature: 278 K |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD![]() |
Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 70.2 e/Å2 |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |