- EMDB-16353: Structure of SLC40/ferroportin in complex with synthetic nanobody... -
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Entry
Database: EMDB / ID: EMD-16353
Title
Structure of SLC40/ferroportin in complex with synthetic nanobody Sy3 in occluded conformation
Map data
Sample
Complex: Complex of ferroportin with synthetic nanobody
Protein or peptide: Solute carrier family 40 member 1
Protein or peptide: Sybody3
Function / homology
Function and homology information
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 / lymphocyte homeostasis / iron ion transmembrane transporter activity / iron ion transmembrane transport / 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 / lymphocyte homeostasis / iron ion transmembrane transporter activity / iron ion transmembrane transport / ferrous iron transmembrane transporter activity / endothelium development / peptide hormone binding / establishment of localization in cell / Iron uptake and transport / multicellular organismal-level iron ion homeostasis / synaptic vesicle / basolateral plasma membrane / intracellular iron ion homeostasis / transcription by RNA polymerase II / apoptotic process / negative regulation of apoptotic process / positive regulation of transcription by RNA polymerase II / nucleoplasm / membrane / identical protein binding / metal ion binding / plasma membrane / cytosol / cytoplasm Similarity search - Function
Journal: Elife / Year: 2023 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.
Entire : Complex of ferroportin with synthetic nanobody
Entire
Name: Complex of ferroportin with synthetic nanobody
Components
Complex: Complex of ferroportin with synthetic nanobody
Protein or peptide: Solute carrier family 40 member 1
Protein or peptide: Sybody3
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Supramolecule #1: Complex of ferroportin with synthetic nanobody
Supramolecule
Name: Complex of ferroportin with synthetic nanobody / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: all 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
Source (natural)
Organism: Homo sapiens (human)
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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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