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- PDB-6fo6: CryoEM structure of bovine cytochrome bc1 in complex with the ant... -

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Basic information

Entry
Database: PDB / ID: 6fo6
TitleCryoEM structure of bovine cytochrome bc1 in complex with the anti-malarial inhibitor SCR0911
Components
  • (Cytochrome b-c1 complex subunit ...) x 7
  • Cytochrome b
  • Cytochrome c1, heme protein, mitochondrial
KeywordsMEMBRANE PROTEIN / Cryo-EM / Inhibitor binding / cytochrome bc1
Function / homology
Function and homology information


Complex III assembly / respiratory chain complex III / Respiratory electron transport / : / quinol-cytochrome-c reductase / ubiquinol-cytochrome-c reductase activity / mitochondrial electron transport, ubiquinol to cytochrome c / ubiquinone binding / Mitochondrial protein degradation / : ...Complex III assembly / respiratory chain complex III / Respiratory electron transport / : / quinol-cytochrome-c reductase / ubiquinol-cytochrome-c reductase activity / mitochondrial electron transport, ubiquinol to cytochrome c / ubiquinone binding / Mitochondrial protein degradation / : / respiratory electron transport chain / mitochondrial membrane / metalloendopeptidase activity / 2 iron, 2 sulfur cluster binding / mitochondrial inner membrane / oxidoreductase activity / heme binding / mitochondrion / proteolysis / membrane / metal ion binding
Similarity search - Function
Ubiquinol-cytochrome c reductase 8kDa, N-terminal / Ubiquinol-cytochrome c reductase 8 kDa, N-terminal / Cytochrome b-c1 complex, subunit 6 / Globular protein, non-globular alpha/beta subunit / Cytochrome b-c1 complex subunit 8 / UcrQ family / Cytochrome bc1 complex subunit Rieske, transmembrane domain superfamily / Cytochrome b-c1 complex subunit 7 / Cytochrome b-c1 complex subunit 7 superfamily / Ubiquinol-cytochrome C reductase complex 14kD subunit ...Ubiquinol-cytochrome c reductase 8kDa, N-terminal / Ubiquinol-cytochrome c reductase 8 kDa, N-terminal / Cytochrome b-c1 complex, subunit 6 / Globular protein, non-globular alpha/beta subunit / Cytochrome b-c1 complex subunit 8 / UcrQ family / Cytochrome bc1 complex subunit Rieske, transmembrane domain superfamily / Cytochrome b-c1 complex subunit 7 / Cytochrome b-c1 complex subunit 7 superfamily / Ubiquinol-cytochrome C reductase complex 14kD subunit / Cytochrome b-c1 complex subunit 9 / Cytochrome b-c1 complex subunit 8 superfamily / Cytochrome b-c1 complex subunit 9 superfamily / Ubiquinol-cytochrome C reductase, UQCRX/QCR9 like / Cytochrome b-c1 complex subunit Rieske, transmembrane domain / Ubiquinol cytochrome reductase transmembrane region / Ubiquinol-cytochrome C reductase hinge domain / Ubiquinol-cytochrome C reductase hinge domain superfamily / Ubiquinol-cytochrome C reductase hinge protein / Cytochrome c1, transmembrane anchor, C-terminal / : / Cytochrome b / : / Ubiquinol-cytochrome c reductase, iron-sulphur subunit / Cytochrome c1 / Cytochrome C1 family / : / Cytochrome b/b6, C-terminal / Cytochrome b(C-terminal)/b6/petD / Cytochrome b/b6 C-terminal region profile. / Cytochrome b/b6, C-terminal domain superfamily / Cytochrome b/b6/petB / Peptidase M16, zinc-binding site / Insulinase family, zinc-binding region signature. / Rieske iron-sulphur protein, C-terminal / Cytochrome b/b6, N-terminal / Cytochrome b/b6-like domain superfamily / Cytochrome b/b6 N-terminal region profile. / Di-haem cytochrome, transmembrane / Rieske iron-sulphur protein / Peptidase M16, C-terminal / Peptidase M16 inactive domain / Peptidase M16, N-terminal / Insulinase (Peptidase family M16) / Metalloenzyme, LuxS/M16 peptidase-like / Rieske [2Fe-2S] domain / Rieske [2Fe-2S] iron-sulphur domain / Rieske [2Fe-2S] iron-sulfur domain profile. / Rieske [2Fe-2S] iron-sulphur domain superfamily / Cytochrome c family profile. / Cytochrome c-like domain / Cytochrome c-like domain superfamily
Similarity search - Domain/homology
Chem-DY2 / HEME C / PROTOPORPHYRIN IX CONTAINING FE / Cytochrome c1, heme protein, mitochondrial / Cytochrome b-c1 complex subunit 6, mitochondrial / Cytochrome b-c1 complex subunit 7 / Cytochrome b-c1 complex subunit 9 / Cytochrome b / Cytochrome b-c1 complex subunit 8 / Cytochrome b-c1 complex subunit Rieske, mitochondrial ...Chem-DY2 / HEME C / PROTOPORPHYRIN IX CONTAINING FE / Cytochrome c1, heme protein, mitochondrial / Cytochrome b-c1 complex subunit 6, mitochondrial / Cytochrome b-c1 complex subunit 7 / Cytochrome b-c1 complex subunit 9 / Cytochrome b / Cytochrome b-c1 complex subunit 8 / Cytochrome b-c1 complex subunit Rieske, mitochondrial / Cytochrome b-c1 complex subunit 2, mitochondrial / Cytochrome b-c1 complex subunit 1, mitochondrial
Similarity search - Component
Biological speciesBos taurus (cattle)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.1 Å
AuthorsJohnson, R.M. / Amporndanai, K. / O'Neill, P.M. / Fishwick, C.W.G. / Jamson, A.H. / Rawson, S.D. / Hasnain, S.S. / Antonyuk, S.V. / Muench, S.P.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome Trust109158/B/15/Z United Kingdom
CitationJournal: IUCrJ / Year: 2018
Title: X-ray and cryo-EM structures of inhibitor-bound cytochrome complexes for structure-based drug discovery.
Authors: Kangsa Amporndanai / Rachel M Johnson / Paul M O'Neill / Colin W G Fishwick / Alexander H Jamson / Shaun Rawson / Stephen P Muench / S Samar Hasnain / Svetlana V Antonyuk /
Abstract: Cytochrome , a dimeric multi-subunit electron-transport protein embedded in the inner mitochondrial membrane, is a major drug target for the treatment and prevention of malaria and toxoplasmosis. ...Cytochrome , a dimeric multi-subunit electron-transport protein embedded in the inner mitochondrial membrane, is a major drug target for the treatment and prevention of malaria and toxoplasmosis. Structural studies of cytochrome from mammalian homologues co-crystallized with lead compounds have underpinned structure-based drug design to develop compounds with higher potency and selectivity. However, owing to the limited amount of cytochrome that may be available from parasites, all efforts have been focused on homologous cytochrome complexes from mammalian species, which has resulted in the failure of some drug candidates owing to toxicity in the host. Crystallographic studies of the native parasite proteins are not feasible owing to limited availability of the proteins. Here, it is demonstrated that cytochrome is highly amenable to single-particle cryo-EM (which uses significantly less protein) by solving the apo and two inhibitor-bound structures to ∼4.1 Å resolution, revealing clear inhibitor density at the binding site. Therefore, cryo-EM is proposed as a viable alternative method for structure-based drug discovery using both host and parasite enzymes.
History
DepositionFeb 6, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 28, 2018Provider: repository / Type: Initial release
Revision 1.1Mar 14, 2018Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_volume ..._citation.journal_abbrev / _citation.journal_volume / _citation.title / _citation_author.name
Revision 1.2May 30, 2018Group: Data collection / Database references / Structure summary
Category: audit_author / citation / citation_author
Item: _audit_author.name / _citation.journal_abbrev ..._audit_author.name / _citation.journal_abbrev / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.3Dec 11, 2019Group: Other / Category: atom_sites / cell
Item: _atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] ..._atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] / _atom_sites.fract_transf_matrix[3][3] / _cell.Z_PDB
Revision 1.4Nov 20, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update

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Structure visualization

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Assembly

Deposited unit
E: Cytochrome b-c1 complex subunit Rieske, mitochondrial
A: Cytochrome b-c1 complex subunit 1, mitochondrial
B: Cytochrome b-c1 complex subunit 2, mitochondrial
C: Cytochrome b
D: Cytochrome c1, heme protein, mitochondrial
F: Cytochrome b-c1 complex subunit 7
G: Cytochrome b-c1 complex subunit 8
H: Cytochrome b-c1 complex subunit 6, mitochondrial
J: Cytochrome b-c1 complex subunit 9
R: Cytochrome b-c1 complex subunit Rieske, mitochondrial
N: Cytochrome b-c1 complex subunit 1, mitochondrial
O: Cytochrome b-c1 complex subunit 2, mitochondrial
P: Cytochrome b
Q: Cytochrome c1, heme protein, mitochondrial
S: Cytochrome b-c1 complex subunit 7
T: Cytochrome b-c1 complex subunit 8
U: Cytochrome b-c1 complex subunit 6, mitochondrial
W: Cytochrome b-c1 complex subunit 9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)504,35326
Polymers499,79818
Non-polymers4,5568
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area72780 Å2
ΔGint-520 kcal/mol
Surface area160460 Å2
MethodPISA

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Components

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Cytochrome b-c1 complex subunit ... , 7 types, 14 molecules ERANBOFSGTHUJW

#1: Protein Cytochrome b-c1 complex subunit Rieske, mitochondrial / Complex III subunit 5 / Cytochrome b-c1 complex subunit 5 / Rieske iron-sulfur protein / RISP / ...Complex III subunit 5 / Cytochrome b-c1 complex subunit 5 / Rieske iron-sulfur protein / RISP / Rieske protein UQCRFS1 / Ubiquinol-cytochrome c reductase iron-sulfur subunit


Mass: 29586.842 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / References: UniProt: P13272, quinol-cytochrome-c reductase
#2: Protein Cytochrome b-c1 complex subunit 1, mitochondrial / Complex III subunit 1 / Core protein I / Ubiquinol-cytochrome-c reductase complex core protein 1


Mass: 52796.410 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / References: UniProt: P31800
#3: Protein Cytochrome b-c1 complex subunit 2, mitochondrial / Complex III subunit 2 / Core protein II / Ubiquinol-cytochrome-c reductase complex core protein 2


Mass: 48203.434 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / References: UniProt: P23004
#6: Protein Cytochrome b-c1 complex subunit 7 / Complex III subunit 7 / Complex III subunit VII / QP-C / Ubiquinol-cytochrome c reductase complex ...Complex III subunit 7 / Complex III subunit VII / QP-C / Ubiquinol-cytochrome c reductase complex 14 kDa protein


Mass: 13502.387 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / References: UniProt: P00129
#7: Protein Cytochrome b-c1 complex subunit 8 / Complex III subunit 8 / Complex III subunit VIII / Ubiquinol-cytochrome c reductase complex 9.5 kDa ...Complex III subunit 8 / Complex III subunit VIII / Ubiquinol-cytochrome c reductase complex 9.5 kDa protein / Ubiquinol-cytochrome c reductase complex ubiquinone-binding protein QP-C


Mass: 9737.223 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / References: UniProt: P13271
#8: Protein Cytochrome b-c1 complex subunit 6, mitochondrial / Complex III subunit 6 / Complex III subunit VIII / Cytochrome c1 non-heme 11 kDa protein / ...Complex III subunit 6 / Complex III subunit VIII / Cytochrome c1 non-heme 11 kDa protein / Mitochondrial hinge protein / Ubiquinol-cytochrome c reductase complex 11 kDa protein


Mass: 10638.744 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / References: UniProt: P00126
#9: Protein Cytochrome b-c1 complex subunit 9 / Complex III subunit 9 / Complex III subunit X / Cytochrome c1 non-heme 7 kDa protein / Ubiquinol- ...Complex III subunit 9 / Complex III subunit X / Cytochrome c1 non-heme 7 kDa protein / Ubiquinol-cytochrome c reductase complex 7.2 kDa protein


Mass: 7469.621 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / References: UniProt: P00130

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Protein , 2 types, 4 molecules CPDQ

#4: Protein Cytochrome b / Complex III subunit 3 / Complex III subunit III / Cytochrome b-c1 complex subunit 3 / Ubiquinol- ...Complex III subunit 3 / Complex III subunit III / Cytochrome b-c1 complex subunit 3 / Ubiquinol-cytochrome-c reductase complex cytochrome b subunit


Mass: 42620.340 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / References: UniProt: P00157
#5: Protein Cytochrome c1, heme protein, mitochondrial / Complex III subunit 4 / Complex III subunit IV / Cytochrome b-c1 complex subunit 4 / Ubiquinol- ...Complex III subunit 4 / Complex III subunit IV / Cytochrome b-c1 complex subunit 4 / Ubiquinol-cytochrome-c reductase complex cytochrome c1 subunit / Cytochrome c-1


Mass: 35343.770 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / References: UniProt: P00125

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Non-polymers , 3 types, 8 molecules

#10: Chemical
ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#11: Chemical ChemComp-DY2 / 7-methoxy-3-methyl-2-[5-[4-(trifluoromethyloxy)phenyl]pyridin-3-yl]quinolin-4-ol


Mass: 426.388 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H17F3N2O3
#12: Chemical ChemComp-HEC / HEME C


Mass: 618.503 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H34FeN4O4

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Details

Has protein modificationY

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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: Cytochrome bc1 in complex with the antimalarial inhibitor SCR0911
Type: COMPLEX / Entity ID: #1-#9 / Source: NATURAL
Molecular weightValue: 0.48 MDa / Experimental value: YES
Source (natural)Organism: Bos taurus (cattle) / Cellular location: Mitochondria / Organ: Heart
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
125 mMTris-HCl1
2100 mMSodium chlorideNaCl1
30.5 mMEDTA1
40.01 %LMNG1
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K
Details: blot for 6 seconds with a blot force of 6 before plunge-freezing

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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 FIELD / Nominal magnification: 79000 X / Nominal defocus max: 4000 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 2 sec. / Electron dose: 85 e/Å2 / Detector mode: INTEGRATING / Film or detector model: FEI FALCON III (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 7893

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Processing

SoftwareName: PHENIX / Version: 1.11.1_2575: / Classification: refinement
EM software
IDNameVersionCategory
2EPUimage acquisition
4GctfCTF correction
7MDFFmodel fitting
9PHENIXmodel refinement
10RELION2initial Euler assignment
11RELION2final Euler assignment
12RELION2classification
13RELION23D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 629258
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 4.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 114130 / Algorithm: FOURIER SPACE / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00861620
ELECTRON MICROSCOPYf_angle_d1.017111167
ELECTRON MICROSCOPYf_dihedral_angle_d5.47224726
ELECTRON MICROSCOPYf_chiral_restr0.0634694
ELECTRON MICROSCOPYf_plane_restr0.0049390

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