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- EMDB-0560: Structure of the human frataxin-bound iron-sulfur cluster assembl... -

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Entry
Database: EMDB / ID: EMD-0560
TitleStructure of the human frataxin-bound iron-sulfur cluster assembly complex
Map dataHuman frataxin-bound iron-sulfur cluster assembly complex
Sample
  • Complex: The human frataxin-bound iron-sulfur cluster assembly complex
    • Protein or peptide: Cysteine desulfurase, mitochondrial
    • Protein or peptide: LYR motif-containing protein 4
    • Protein or peptide: Acyl carrier protein
    • Protein or peptide: Iron-sulfur cluster assembly enzyme ISCU, mitochondrial
    • Protein or peptide: Frataxin, mitochondrial
  • Ligand: PYRIDOXAL-5'-PHOSPHATEPyridoxal phosphate
  • Ligand: S-[2-({N-[(2R)-2-hydroxy-3,3-dimethyl-4-(phosphonooxy)butanoyl]-beta-alanyl}amino)ethyl] dodecanethioate
  • Ligand: ZINC ION
Function / homology
Function and homology information


negative regulation of iron ion import across plasma membrane / molybdopterin cofactor metabolic process / regulation of ferrochelatase activity / Molybdenum cofactor biosynthesis / [4Fe-4S] cluster assembly / proprioception / iron incorporation into metallo-sulfur cluster / positive regulation of lyase activity / positive regulation of succinate dehydrogenase activity / L-cysteine desulfurase complex ...negative regulation of iron ion import across plasma membrane / molybdopterin cofactor metabolic process / regulation of ferrochelatase activity / Molybdenum cofactor biosynthesis / [4Fe-4S] cluster assembly / proprioception / iron incorporation into metallo-sulfur cluster / positive regulation of lyase activity / positive regulation of succinate dehydrogenase activity / L-cysteine desulfurase complex / Mitochondrial iron-sulfur cluster biogenesis / mitochondrial iron-sulfur cluster assembly complex / positive regulation of aconitate hydratase activity / positive regulation of mitochondrial electron transport, NADH to ubiquinone / iron chaperone activity / cysteine desulfurase / cysteine desulfurase activity / negative regulation of organ growth / iron-sulfur cluster assembly complex / Mo-molybdopterin cofactor biosynthetic process / Mitochondrial protein import / [2Fe-2S] cluster assembly / adult walking behavior / oxidative phosphorylation / response to iron ion / embryo development ending in birth or egg hatching / iron-sulfur cluster assembly / acyl carrier activity / heme biosynthetic process / muscle cell cellular homeostasis / negative regulation of multicellular organism growth / organ growth / positive regulation of catalytic activity / ferroxidase / iron-sulfur cluster binding / negative regulation of release of cytochrome c from mitochondria / ferroxidase activity / protein autoprocessing / mitochondrion organization / ferric iron binding / ferrous iron binding / 2 iron, 2 sulfur cluster binding / cellular response to hydrogen peroxide / pyridoxal phosphate binding / Maturation of replicase proteins / iron ion transport / positive regulation of cell growth / intracellular iron ion homeostasis / molecular adaptor activity / nuclear body / mitochondrial matrix / iron ion binding / centrosome / positive regulation of cell population proliferation / negative regulation of apoptotic process / protein homodimerization activity / mitochondrion / zinc ion binding / nucleoplasm / metal ion binding / nucleus / cytosol / cytoplasm
Similarity search - Function
LYRM4, LYR domain / ISC system FeS cluster assembly, IscU scaffold / Frataxin / Cysteine desulfurase IscS / Frataxin/CyaY / Frataxin conserved site / Frataxin-like domain / Frataxin family signature. / Frataxin family profile. / Frataxin-like domain ...LYRM4, LYR domain / ISC system FeS cluster assembly, IscU scaffold / Frataxin / Cysteine desulfurase IscS / Frataxin/CyaY / Frataxin conserved site / Frataxin-like domain / Frataxin family signature. / Frataxin family profile. / Frataxin-like domain / NIF system FeS cluster assembly, NifU, N-terminal / NifU-like N terminal domain / Frataxin/CyaY superfamily / Cysteine desulfurase / Aminotransferase class-V, pyridoxal-phosphate binding site / Aminotransferases class-V pyridoxal-phosphate attachment site. / Aminotransferase class V domain / Aminotransferase class-V / Complex 1 LYR protein domain / Complex 1 protein (LYR family) / Acyl carrier protein (ACP) / Phosphopantetheine attachment site / Phosphopantetheine attachment site. / Phosphopantetheine attachment site / ACP-like superfamily / Carrier protein (CP) domain profile. / Phosphopantetheine binding ACP domain / Pyridoxal phosphate-dependent transferase, small domain / Pyridoxal phosphate-dependent transferase, major domain / Pyridoxal phosphate-dependent transferase
Similarity search - Domain/homology
Acyl carrier protein / Frataxin, mitochondrial / Iron-sulfur cluster assembly enzyme ISCU / LYR motif-containing protein 4 / Cysteine desulfurase
Similarity search - Component
Biological speciesHomo sapiens (human) / Escherichia coli (E. coli)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsFox NG / Yu X / Xidong F / Alain M / Joseph N / Claire SD / Christine B / Han S / Yue WW
CitationJournal: Nat Commun / Year: 2019
Title: Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism.
Authors: Nicholas G Fox / Xiaodi Yu / Xidong Feng / Henry J Bailey / Alain Martelli / Joseph F Nabhan / Claire Strain-Damerell / Christine Bulawa / Wyatt W Yue / Seungil Han /
Abstract: The core machinery for de novo biosynthesis of iron-sulfur clusters (ISC), located in the mitochondria matrix, is a five-protein complex containing the cysteine desulfurase NFS1 that is activated by ...The core machinery for de novo biosynthesis of iron-sulfur clusters (ISC), located in the mitochondria matrix, is a five-protein complex containing the cysteine desulfurase NFS1 that is activated by frataxin (FXN), scaffold protein ISCU, accessory protein ISD11, and acyl-carrier protein ACP. Deficiency in FXN leads to the loss-of-function neurodegenerative disorder Friedreich's ataxia (FRDA). Here the 3.2 Å resolution cryo-electron microscopy structure of the FXN-bound active human complex, containing two copies of the NFS1-ISD11-ACP-ISCU-FXN hetero-pentamer, delineates the interactions of FXN with other component proteins of the complex. FXN binds at the interface of two NFS1 and one ISCU subunits, modifying the local environment of a bound zinc ion that would otherwise inhibit NFS1 activity in complexes without FXN. Our structure reveals how FXN facilitates ISC production through stabilizing key loop conformations of NFS1 and ISCU at the protein-protein interfaces, and suggests how FRDA clinical mutations affect complex formation and FXN activation.
History
DepositionFeb 14, 2019-
Header (metadata) releaseMar 13, 2019-
Map releaseMay 22, 2019-
UpdateJul 10, 2019-
Current statusJul 10, 2019Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0425
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.0425
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6nzu
  • Surface level: 0.0425
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_0560.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHuman frataxin-bound iron-sulfur cluster assembly complex
Voxel sizeX=Y=Z: 1.086 Å
Density
Contour LevelBy AUTHOR: 0.0425 / Movie #1: 0.0425
Minimum - Maximum-0.20349748 - 0.33728746
Average (Standard dev.)-0.00007063915 (±0.011196485)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 217.2 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0861.0861.086
M x/y/z200200200
origin x/y/z0.0000.0000.000
length x/y/z217.200217.200217.200
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS200200200
D min/max/mean-0.2030.337-0.000

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Supplemental data

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Mask #1

Fileemd_0560_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: Human frataxin-bound iron-sulfur cluster assembly complex, half map 1

Fileemd_0560_half_map_1.map
AnnotationHuman frataxin-bound iron-sulfur cluster assembly complex, half map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: Human frataxin-bound iron-sulfur cluster assembly complex, half map 2

Fileemd_0560_half_map_2.map
AnnotationHuman frataxin-bound iron-sulfur cluster assembly complex, half map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Sample components

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Entire : The human frataxin-bound iron-sulfur cluster assembly complex

EntireName: The human frataxin-bound iron-sulfur cluster assembly complex
Components
  • Complex: The human frataxin-bound iron-sulfur cluster assembly complex
    • Protein or peptide: Cysteine desulfurase, mitochondrial
    • Protein or peptide: LYR motif-containing protein 4
    • Protein or peptide: Acyl carrier protein
    • Protein or peptide: Iron-sulfur cluster assembly enzyme ISCU, mitochondrial
    • Protein or peptide: Frataxin, mitochondrial
  • Ligand: PYRIDOXAL-5'-PHOSPHATEPyridoxal phosphate
  • Ligand: S-[2-({N-[(2R)-2-hydroxy-3,3-dimethyl-4-(phosphonooxy)butanoyl]-beta-alanyl}amino)ethyl] dodecanethioate
  • Ligand: ZINC ION

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Supramolecule #1: The human frataxin-bound iron-sulfur cluster assembly complex

SupramoleculeName: The human frataxin-bound iron-sulfur cluster assembly complex
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
Molecular weightExperimental: 186 KDa

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Macromolecule #1: Cysteine desulfurase, mitochondrial

MacromoleculeName: Cysteine desulfurase, mitochondrial / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: cysteine desulfurase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 44.850371 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString: MLRPLYMDVQ ATTPLDPRVL DAMLPYLINY YGNPHSRTHA YGWESEAAME RARQQVASLI GADPREIIFT SGATESNNIA IKGVARFYR SRKKHLITTQ TEHKCVLDSC RSLEAEGFQV TYLPVQKSGI IDLKELEAAI QPDTSLVSVM TVNNEIGVKQ P IAEIGRIC ...String:
MLRPLYMDVQ ATTPLDPRVL DAMLPYLINY YGNPHSRTHA YGWESEAAME RARQQVASLI GADPREIIFT SGATESNNIA IKGVARFYR SRKKHLITTQ TEHKCVLDSC RSLEAEGFQV TYLPVQKSGI IDLKELEAAI QPDTSLVSVM TVNNEIGVKQ P IAEIGRIC SSRKVYFHTD AAQAVGKIPL DVNDMKIDLM SISGHKIYGP KGVGAIYIRR RPRVRVEALQ SGGGQERGMR SG TVPTPLV VGLGAACEVA QQEMEYDHKR ISKLSERLIQ NIMKSLPDVV MNGDPKHHYP GCINLSFAYV EGESLLMALK DVA LSSGSA CTSASLEPSY VLRAIGTDED LAHSSIRFGI GRFTTEEEVD YTVEKCIQHV KRLREMSPLW EMVQDGIDLK SIKW TQH

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Macromolecule #2: LYR motif-containing protein 4

MacromoleculeName: LYR motif-containing protein 4 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 10.850562 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString:
SMAASSRAQV LALYRAMLRE SKRFSAYNYR TYAVRRIRDA FRENKNVKDP VEIQTLVNKA KRDLGVIRRQ VHIGQLYSTD KLIIENRDM PRT

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Macromolecule #3: Acyl carrier protein

MacromoleculeName: Acyl carrier protein / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Escherichia coli (E. coli)
Molecular weightTheoretical: 8.251055 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString:
MSTIEERVKK IIGEQLGVKQ EEVTNNASFV EDLGADSLDT VELVMALEEE FDTEIPDEEA EKITTVQAAI DYIN

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Macromolecule #4: Iron-sulfur cluster assembly enzyme ISCU, mitochondrial

MacromoleculeName: Iron-sulfur cluster assembly enzyme ISCU, mitochondrial
type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.41258 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString:
MYHKKVVDHY ENPRNVGSLD KTSKNVGTGL VGAPACGDVM KLQIQVDEKG KIVDARFKTF GCGSAIASSS LATEWVKGKT VEEALTIKN TDIAKELCLP PVKLHCSMLA EDAIKAALAD YKLKQ

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Macromolecule #5: Frataxin, mitochondrial

MacromoleculeName: Frataxin, mitochondrial / type: protein_or_peptide / ID: 5 / Number of copies: 2 / Enantiomer: LEVO / EC number: ferroxidase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.501001 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString:
SMSGTLGHPG SLDETTYERL AEETLDSLAE FFEDLADKPY TFEDYDVSFG SGVLTVKLGG DLGTYVINKQ TPNKQIWLSS PSSGPKRYD WTGKNWVYSH DGVSLHELLA AELTKALKTK LDLSSLAYSG KDA

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Macromolecule #6: PYRIDOXAL-5'-PHOSPHATE

MacromoleculeName: PYRIDOXAL-5'-PHOSPHATE / type: ligand / ID: 6 / Number of copies: 2 / Formula: PLP
Molecular weightTheoretical: 247.142 Da
Chemical component information

ChemComp-PLP:
PYRIDOXAL-5'-PHOSPHATE / Pyridoxal phosphate

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Macromolecule #7: S-[2-({N-[(2R)-2-hydroxy-3,3-dimethyl-4-(phosphonooxy)butanoyl]-b...

MacromoleculeName: S-[2-({N-[(2R)-2-hydroxy-3,3-dimethyl-4-(phosphonooxy)butanoyl]-beta-alanyl}amino)ethyl] dodecanethioate
type: ligand / ID: 7 / Number of copies: 2 / Formula: 8Q1
Molecular weightTheoretical: 540.651 Da
Chemical component information

ChemComp-8Q1:
S-[2-({N-[(2R)-2-hydroxy-3,3-dimethyl-4-(phosphonooxy)butanoyl]-beta-alanyl}amino)ethyl] dodecanethioate

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Macromolecule #8: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 8 / Number of copies: 2 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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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

BufferpH: 7.5
GridDetails: unspecified
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 42.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 267153
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

chain_id: A

chain_id: A

chain_id: B

chain_id: C

chain_id: D
SoftwareName: Coot
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-6nzu:
Structure of the human frataxin-bound iron-sulfur cluster assembly complex

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