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- EMDB-21599: Structure of human ferroportin bound to hepcidin and cobalt in li... -

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Basic information

Entry
Database: EMDB / ID: EMD-21599
TitleStructure of human ferroportin bound to hepcidin and cobalt in lipid nanodisc
Map datahuman ferroportin bound to hepcidin and cobalt in lipid nanodisc
Sample
  • Complex: Ferroportin-Fab45D8 complex
    • Complex: Ferroportin-hepcidin complex
      • Protein or peptide: Hepcidin
      • Protein or peptide: Solute carrier family 40 member 1
    • Complex: Fab45D8
      • Protein or peptide: Fab45D8 Light Chain
      • Protein or peptide: Fab45D8 Heavy Chain
  • Ligand: (1S)-2-{[{[(2S)-2,3-DIHYDROXYPROPYL]OXY}(HYDROXY)PHOSPHORYL]OXY}-1-[(PENTANOYLOXY)METHYL]ETHYL OCTANOATE
  • Ligand: COBALT (II) ION
  • Ligand: water
Keywordsferroportin / transporter / iron / hepcidin / TRANSLOCASE-IMMUNE SYSTEM-HORMONE complex
Function / homology
Function and homology information


negative regulation of iron export across plasma membrane / negative regulation of intestinal absorption / 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 / ferrous iron transmembrane transporter activity ...negative regulation of iron export across plasma membrane / negative regulation of intestinal absorption / 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 / ferrous iron transmembrane transporter activity / endothelium development / iron ion transmembrane transporter activity / iron ion transmembrane transport / macrophage activation / positive regulation of macrophage activation / response to iron ion / negative regulation of iron ion transmembrane transport / negative regulation of bone resorption / myeloid cell homeostasis / transporter regulator activity / peptide hormone binding / cell surface receptor signaling pathway via JAK-STAT / defense response to fungus / establishment of localization in cell / Iron uptake and transport / protein catabolic process / hormone activity / multicellular organismal-level iron ion homeostasis / negative regulation of inflammatory response / synaptic vesicle / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / basolateral plasma membrane / killing of cells of another organism / transcription by RNA polymerase II / intracellular iron ion homeostasis / defense response to bacterium / immune response / inflammatory response / copper ion binding / apoptotic process / negative regulation of apoptotic process / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / extracellular space / extracellular region / nucleoplasm / metal ion binding / identical protein binding / nucleus / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Hepcidin / Hepcidin / Ferroportin-1 / Ferroportin1 (FPN1) / MFS transporter superfamily
Similarity search - Domain/homology
Hepcidin / Ferroportin
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsBillesboelle CB / Azumaya CM
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)1DP5OD023048 United States
CitationJournal: Nature / Year: 2020
Title: Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms.
Authors: Christian B Billesbølle / Caleigh M Azumaya / Rachael C Kretsch / Alexander S Powers / Shane Gonen / Simon Schneider / Tara Arvedson / Ron O Dror / Yifan Cheng / Aashish Manglik /
Abstract: The serum level of iron in humans is tightly controlled by the action of the hormone hepcidin on the iron efflux transporter ferroportin. Hepcidin regulates iron absorption and recycling by inducing ...The serum level of iron in humans is tightly controlled by the action of the hormone hepcidin on the iron efflux transporter ferroportin. Hepcidin regulates iron absorption and recycling by inducing the internalization and degradation of ferroportin. Aberrant ferroportin activity can lead to diseases of iron overload, such as haemochromatosis, or iron limitation anaemias. Here we determine cryogenic electron microscopy structures of ferroportin in lipid nanodiscs, both in the apo state and in complex with hepcidin and the iron mimetic cobalt. These structures and accompanying molecular dynamics simulations identify two metal-binding sites within the N and C domains of ferroportin. Hepcidin binds ferroportin in an outward-open conformation and completely occludes the iron efflux pathway to inhibit transport. The carboxy terminus of hepcidin directly contacts the divalent metal in the ferroportin C domain. Hepcidin binding to ferroportin is coupled to iron binding, with an 80-fold increase in hepcidin affinity in the presence of iron. These results suggest a model for hepcidin regulation of ferroportin, in which only ferroportin molecules loaded with iron are targeted for degradation. More broadly, our structural and functional insights may enable more targeted manipulation of the hepcidin-ferroportin axis in disorders of iron homeostasis.
History
DepositionMar 27, 2020-
Header (metadata) releaseSep 9, 2020-
Map releaseSep 9, 2020-
UpdateMay 28, 2025-
Current statusMay 28, 2025Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 5
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 5
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6wbv
  • Surface level: 5
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21599.png

Downloads & links

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Map

FileDownload / File: emd_21599.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationhuman ferroportin bound to hepcidin and cobalt in lipid nanodisc
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 300 pix.
= 250.2 Å		0.83 Å/pix.
x 300 pix.
= 250.2 Å		0.83 Å/pix.
x 300 pix.
= 250.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.834 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 5.0 / Movie #1: 5
Minimum - Maximum-20.142084000000001 - 37.044902999999998
Average (Standard dev.)-0.012805424 (±0.9586738)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 250.2 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8340.8340.834
M x/y/z300300300
origin x/y/z0.0000.0000.000
length x/y/z250.200250.200250.200
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ500500500
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS300300300
D min/max/mean-20.14237.045-0.013

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Supplemental data

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Half map: #1

Fileemd_21599_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_21599_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Ferroportin-Fab45D8 complex

EntireName: Ferroportin-Fab45D8 complex
Components
  • Complex: Ferroportin-Fab45D8 complex
    • Complex: Ferroportin-hepcidin complex
      • Protein or peptide: Hepcidin
      • Protein or peptide: Solute carrier family 40 member 1
    • Complex: Fab45D8
      • Protein or peptide: Fab45D8 Light Chain
      • Protein or peptide: Fab45D8 Heavy Chain
  • Ligand: (1S)-2-{[{[(2S)-2,3-DIHYDROXYPROPYL]OXY}(HYDROXY)PHOSPHORYL]OXY}-1-[(PENTANOYLOXY)METHYL]ETHYL OCTANOATE
  • Ligand: COBALT (II) ION
  • Ligand: water

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Supramolecule #1: Ferroportin-Fab45D8 complex

SupramoleculeName: Ferroportin-Fab45D8 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4

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Supramolecule #2: Ferroportin-hepcidin complex

SupramoleculeName: Ferroportin-hepcidin complex / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Fab45D8

SupramoleculeName: Fab45D8 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3-#4
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Hepcidin

MacromoleculeName: Hepcidin / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 2.802455 KDa
SequenceString:
DTHFPICIFC CGCCHRSKCG MCCKT

UniProtKB: Hepcidin

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Macromolecule #2: Solute carrier family 40 member 1

MacromoleculeName: Solute carrier family 40 member 1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: Translocases
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 66.349898 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MTRAGDHNRQ RGCCGSLADY LTSAKFLLYL GHSLSTWGDR MWHFAVSVFL VELYGNSLLL TAVYGLVVAG SVLVLGAIIG DWVDKNARL KVAQTSLVVQ NVSVILCGII LMMVFLHKHE LLTMYHGWVL TSCYILIITI ANIANLASTA TAITIQRDWI V VVAGEDRS ...String:
MTRAGDHNRQ RGCCGSLADY LTSAKFLLYL GHSLSTWGDR MWHFAVSVFL VELYGNSLLL TAVYGLVVAG SVLVLGAIIG DWVDKNARL KVAQTSLVVQ NVSVILCGII LMMVFLHKHE LLTMYHGWVL TSCYILIITI ANIANLASTA TAITIQRDWI V VVAGEDRS KLANMNATIR RIDQLTNILA PMAVGQIMTF GSPVIGCGFI SGWNLVSMCV EYVLLWKVYQ KTPALAVKAG LK EEETELK QLNLHKDTEP KPLEGTHLMG VKDSNIHELE HEQEPTCASQ MAEPFRTFRD GWVSYYNQPV FLAGMGLAFL YMT VLGFDC ITTGYAYTQG LSGSILSILM GASAITGIMG TVAFTWLRRK CGLVRTGLIS GLAQLSCLIL CVISVFMPGS PLDL SVSPF EDIRSRFIQG ESITPTKIPE ITTEIYMSNG SNSANIVPET SPESVPIISV SLLFAGVIAA RIGLWSFDLT VTQLL QENV IESERGIING VQNSMNYLLD LLHFIMVILA PNPEAFGLLV LISVSFVAMG HIMYFRFAQN TLGNKLFACG PDAKEV RKE NQANTSVVGS GLEVLFQGPG AAEDQVDPRL IDGKHHHHHH HH

UniProtKB: Ferroportin

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Macromolecule #3: Fab45D8 Light Chain

MacromoleculeName: Fab45D8 Light Chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 24.008516 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DIVLTQSPAS LPVSLGQRAT ISCRASKSVS ASAYSYMHWY QQKPGQPPKP LIYLASNLES GVPARFSGSG SGTDFTLNIH PVEEEDAAT YYCQHNRELP YTFGGGTKLE IKRADAAPTV SIFPPSSEQL TSGGASVVCF LNNFYPKDIN VKWKIDGSER Q NGVLNSWT ...String:
DIVLTQSPAS LPVSLGQRAT ISCRASKSVS ASAYSYMHWY QQKPGQPPKP LIYLASNLES GVPARFSGSG SGTDFTLNIH PVEEEDAAT YYCQHNRELP YTFGGGTKLE IKRADAAPTV SIFPPSSEQL TSGGASVVCF LNNFYPKDIN VKWKIDGSER Q NGVLNSWT DQDSKDSTYS MSSTLTLTKD EYERHNSYTC EATHKTSTSP IVKSFNRNEC

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Macromolecule #4: Fab45D8 Heavy Chain

MacromoleculeName: Fab45D8 Heavy Chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.852592 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLQESGPG LAKPSQTLSL TCSVTGSSIT SDYWNWIRKF PGNKLEYMGY ISYSGSTYYN PSLKSQISIT RDTSKNHYYL QLNSVTTED TATYYCARQG LRNWYFDVWG TGTTVTVSSA KTTAPSVYPL APVCGGTTGS SVTLGCLVKG YFPEPVTLTW N SGSLSSGV ...String:
EVQLQESGPG LAKPSQTLSL TCSVTGSSIT SDYWNWIRKF PGNKLEYMGY ISYSGSTYYN PSLKSQISIT RDTSKNHYYL QLNSVTTED TATYYCARQG LRNWYFDVWG TGTTVTVSSA KTTAPSVYPL APVCGGTTGS SVTLGCLVKG YFPEPVTLTW N SGSLSSGV HTFPALLQSG LYTLSSSVTV TSNTWPSQTI TCNVAHPASS TKVDKKIEPR VP

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Macromolecule #5: (1S)-2-{[{[(2S)-2,3-DIHYDROXYPROPYL]OXY}(HYDROXY)PHOSPHORYL]OXY}-...

MacromoleculeName: (1S)-2-{[{[(2S)-2,3-DIHYDROXYPROPYL]OXY}(HYDROXY)PHOSPHORYL]OXY}-1-[(PENTANOYLOXY)METHYL]ETHYL OCTANOATE
type: ligand / ID: 5 / Number of copies: 2 / Formula: AGA
Molecular weightTheoretical: 455.457 Da
Chemical component information

ChemComp-AGA:
(1S)-2-{[{[(2S)-2,3-DIHYDROXYPROPYL]OXY}(HYDROXY)PHOSPHORYL]OXY}-1-[(PENTANOYLOXY)METHYL]ETHYL OCTANOATE

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Macromolecule #6: COBALT (II) ION

MacromoleculeName: COBALT (II) ION / type: ligand / ID: 6 / Number of copies: 2 / Formula: CO
Molecular weightTheoretical: 58.933 Da

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Macromolecule #7: water

MacromoleculeName: water / type: ligand / ID: 7 / Number of copies: 11 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1.5 mg/mL
BufferpH: 7.5
GridDetails: unspecified
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 3 / Number real images: 5415 / Average exposure time: 6.0 sec. / Average electron dose: 66.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: -20.0 µm / Nominal defocus min: -8.0 µm / Nominal magnification: 105000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: CTFFIND / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: Ab initio generated 3D model from RELION
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cisTEM / Number images used: 310647
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationSoftware - Name: RELION

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