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Structure paper

TitleStructures of ferroportin in complex with its specific inhibitor vamifeport.
Journal, issue, pagesElife, Vol. 12, Year 2023
Publish dateMar 21, 2023
AuthorsElena Farah Lehmann / Márton Liziczai / Katarzyna Drożdżyk / Patrick Altermatt / Cassiano Langini / Vania Manolova / Hanna Sundstrom / Franz Dürrenberger / Raimund Dutzler / Cristina Manatschal /
PubMed AbstractA 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.
External linksElife / PubMed:36943194 / PubMed Central
MethodsEM (single particle)
Resolution3.24 - 4.09 Å
Structure data

16345

8bzy

EMDB-16345, PDB-8bzy:
Structure of SLC40/ferroportin in complex with vamifeport and synthetic nanobody Sy3 in occluded conformation
Method: EM (single particle) / Resolution: 3.24 Å

16353

8c02

EMDB-16353, PDB-8c02:
Structure of SLC40/ferroportin in complex with synthetic nanobody Sy3 in occluded conformation
Method: EM (single particle) / Resolution: 4.09 Å

16354

8c03

EMDB-16354, PDB-8c03:
Structure of SLC40/ferroportin in complex with vamifeport and synthetic nanobody Sy12 in outward-facing conformation
Method: EM (single particle) / Resolution: 3.89 Å

Chemicals

ChemComp-PLC:
DIUNDECYL PHOSPHATIDYL CHOLINE / phospholipid*YM

ChemComp-SZU:
2-[2-[2-(1~{H}-benzimidazol-2-yl)ethylamino]ethyl]-~{N}-[(3-fluoranylpyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsTRANSPORT PROTEIN / Iron / Inhibitor / SLC40 / Transporter

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