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- PDB-6nzu: Structure of the human frataxin-bound iron-sulfur cluster assembl... -

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Basic information

Entry
Database: PDB / ID: 6nzu
TitleStructure of the human frataxin-bound iron-sulfur cluster assembly complex
Components
  • Acyl carrier protein
  • Cysteine desulfurase, mitochondrial
  • Frataxin, mitochondrial
  • Iron-sulfur cluster assembly enzyme ISCU, mitochondrial
  • LYR motif-containing protein 4
KeywordsTRANSFERASE / OXIDOREDUCTASE / human frataxin-bound iron-sulfur cluster assembly complex
Function / homology
Function and homology information


Molybdenum cofactor biosynthesis / Mitochondrial iron-sulfur cluster biogenesis / Mitochondrial protein import / negative regulation of iron ion import across plasma membrane / L-cysteine desulfurase complex / regulation of ferrochelatase activity / positive regulation of succinate dehydrogenase activity / positive regulation of lyase activity / positive regulation of aconitate hydratase activity / proprioception ...Molybdenum cofactor biosynthesis / Mitochondrial iron-sulfur cluster biogenesis / Mitochondrial protein import / negative regulation of iron ion import across plasma membrane / L-cysteine desulfurase complex / regulation of ferrochelatase activity / positive regulation of succinate dehydrogenase activity / positive regulation of lyase activity / positive regulation of aconitate hydratase activity / proprioception / small molecule metabolic process / iron incorporation into metallo-sulfur cluster / [2Fe-2S] cluster assembly / sulfur amino acid metabolic process / cysteine desulfurase / cysteine desulfurase activity / positive regulation of mitochondrial electron transport, NADH to ubiquinone / molybdopterin cofactor biosynthetic process / iron chaperone activity / negative regulation of organ growth / negative regulation of multicellular organism growth / acyl carrier activity / oxidative phosphorylation / adult walking behavior / Mo-molybdopterin cofactor biosynthetic process / iron-sulfur cluster assembly / embryo development ending in birth or egg hatching / heme biosynthetic process / iron-sulfur cluster binding / response to iron ion / ferroxidase / protein autoprocessing / negative regulation of release of cytochrome c from mitochondria / molecular adaptor activity / ferroxidase activity / positive regulation of catalytic activity / aerobic respiration / ion transport / ferric iron binding / mitochondrion organization / ferrous iron binding / 2 iron, 2 sulfur cluster binding / cellular iron ion homeostasis / cellular response to hydrogen peroxide / 4 iron, 4 sulfur cluster binding / protein-containing complex assembly / pyridoxal phosphate binding / nuclear body / positive regulation of cell growth / mitochondrial matrix / iron ion binding / positive regulation of cell population proliferation / negative regulation of apoptotic process / mitochondrion / protein homodimerization activity / nucleoplasm / metal ion binding / nucleus / cytosol / cytoplasm
Pyridoxal phosphate-dependent transferase / Phosphopantetheine attachment site / Frataxin/CyaY superfamily / Frataxin conserved site / Aminotransferase class-V, pyridoxal-phosphate binding site / ACP-like superfamily / Aminotransferase class-V / Frataxin / Cysteine desulfurase / Phosphopantetheine attachment site ...Pyridoxal phosphate-dependent transferase / Phosphopantetheine attachment site / Frataxin/CyaY superfamily / Frataxin conserved site / Aminotransferase class-V, pyridoxal-phosphate binding site / ACP-like superfamily / Aminotransferase class-V / Frataxin / Cysteine desulfurase / Phosphopantetheine attachment site / Frataxin-like domain / NifU-like N terminal domain / Complex 1 protein (LYR family) / NIF system FeS cluster assembly, NifU, N-terminal / Frataxin/CyaY / Acyl carrier protein (ACP) / Aminotransferase class V domain / Phosphopantetheine attachment site. / Aminotransferases class-V pyridoxal-phosphate attachment site. / Pyridoxal phosphate-dependent transferase domain 1 / Pyridoxal phosphate-dependent transferase, major domain / Frataxin family profile. / Carrier protein (CP) domain profile. / Complex 1 LYR protein / Frataxin family signature. / Phosphopantetheine binding ACP domain / Cysteine desulfurase IscS / ISC system FeS cluster assembly, IscU scaffold
Acyl carrier protein / Frataxin, mitochondrial / Iron-sulfur cluster assembly enzyme ISCU, mitochondrial / LYR motif-containing protein 4 / Cysteine desulfurase, mitochondrial
Biological speciesHomo sapiens (human)
Escherichia coli (E. coli)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsFox, N.G. / Yu, X. / Xidong, F. / Alain, M. / Joseph, N. / Claire, S.D. / Christine, B. / Han, S. / Yue, W.W.
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.
Validation Report
SummaryFull reportAbout validation report
History
DepositionFeb 14, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 22, 2019Provider: repository / Type: Initial release
Revision 1.1May 29, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jul 10, 2019Group: Data collection / Database references ...Data collection / Database references / Source and taxonomy / Structure summary
Category: entity_name_com / entity_src_gen ...entity_name_com / entity_src_gen / struct_ref / struct_ref_seq
Item: _entity_src_gen.gene_src_common_name / _entity_src_gen.pdbx_gene_src_gene ..._entity_src_gen.gene_src_common_name / _entity_src_gen.pdbx_gene_src_gene / _entity_src_gen.pdbx_gene_src_ncbi_taxonomy_id / _entity_src_gen.pdbx_gene_src_scientific_name / _struct_ref.db_code / _struct_ref.db_name / _struct_ref.pdbx_db_accession / _struct_ref.pdbx_seq_one_letter_code / _struct_ref_seq.pdbx_db_accession

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Structure visualization

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Assembly

Deposited unit
A: Cysteine desulfurase, mitochondrial
B: LYR motif-containing protein 4
C: Acyl carrier protein
D: Iron-sulfur cluster assembly enzyme ISCU, mitochondrial
E: Cysteine desulfurase, mitochondrial
F: LYR motif-containing protein 4
G: Acyl carrier protein
H: Iron-sulfur cluster assembly enzyme ISCU, mitochondrial
I: Frataxin, mitochondrial
J: Frataxin, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)185,43816
Polymers183,73110
Non-polymers1,7066
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area27520 Å2
ΔGint-184 kcal/mol
Surface area62340 Å2

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Components

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Protein/peptide , 5 types, 10 molecules AEBFCGDHIJ

#1: Protein/peptide Cysteine desulfurase, mitochondrial /


Mass: 44850.371 Da / Num. of mol.: 2 / Fragment: UNP residues 56-457
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NFS1, NIFS, HUSSY-08
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: Q9Y697, cysteine desulfurase
#2: Protein/peptide LYR motif-containing protein 4


Mass: 10850.562 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LYRM4, C6orf149, ISD11, CGI-203
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: Q9HD34
#3: Protein/peptide Acyl carrier protein / / ACP


Mass: 8251.055 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli (E. coli) / Gene: acpP, DQL48_09575, EOL36_14065
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: A0A437HBF4
#4: Protein/peptide Iron-sulfur cluster assembly enzyme ISCU, mitochondrial / NifU-like N-terminal domain-containing protein / NifU-like protein


Mass: 13412.580 Da / Num. of mol.: 2 / Fragment: UNP residues 35-157
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ISCU, NIFUN
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: Q9H1K1
#5: Protein/peptide Frataxin, mitochondrial / / Friedreich ataxia protein / Fxn


Mass: 14501.001 Da / Num. of mol.: 2 / Fragment: UNP residues 81-210
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FXN, FRDA, X25
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: Q16595, ferroxidase

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Non-polymers , 3 types, 6 molecules

#6: Chemical ChemComp-PLP / PYRIDOXAL-5'-PHOSPHATE / VITAMIN B6 Phosphate


Mass: 247.142 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H10NO6P / Pyridoxal phosphate
#7: Chemical ChemComp-8Q1 / S-[2-({N-[(2R)-2-hydroxy-3,3-dimethyl-4-(phosphonooxy)butanoyl]-beta-alanyl}amino)ethyl] dodecanethioate / S-dodecanoyl-4'-phosphopantetheine


Mass: 540.651 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H45N2O8PS
#8: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn / Zinc

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: The human frataxin-bound iron-sulfur cluster assembly complex
Type: COMPLEX / Entity ID: 1,2,3,4,5 / Source: RECOMBINANT
Molecular weightValue: 0.186 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: unspecified
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 42 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.14_3260: / Classification: refinement
EM software
IDNameCategory
7Cootmodel fitting
8UCSF Chimeramodel fitting
14PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 267153 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model building

3D fitting-ID: 1

IDPDB-IDPdb chain-ID
15KZ5A
25WKPA
35WKPB
45WKPC
55WKPD

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