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- PDB-7tz6: Structure of mitochondrial bc1 in complex with ck-2-68 -

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Basic information

Entry
Database: PDB / ID: 7tz6
TitleStructure of mitochondrial bc1 in complex with ck-2-68
Components
  • (Cytochrome b-c1 complex subunit ...) x 9
  • Cytochrome b
  • Cytochrome c1, heme protein, mitochondrial
KeywordsOXIDOREDUCTASE / Mitochondrial cytochrome bc1 / antimalarial inhibitor / electron transfer
Function / homology
Function and homology information


Respiratory electron transport / : / quinol-cytochrome-c reductase / ubiquinol-cytochrome-c reductase activity / mitochondrial electron transport, ubiquinol to cytochrome c / Mitochondrial protein degradation / : / ubiquinone binding / respiratory electron transport chain / mitochondrial membrane ...Respiratory electron transport / : / quinol-cytochrome-c reductase / ubiquinol-cytochrome-c reductase activity / mitochondrial electron transport, ubiquinol to cytochrome c / Mitochondrial protein degradation / : / ubiquinone binding / 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 / plasma membrane
Similarity search - Function
Cytochrome b-c1 complex subunit 10 / Single alpha-helix domain superfamily / Ubiquinol-cytochrome C reductase complex, 6.4kD protein / Ubiquinol-cytochrome c reductase 8kDa, N-terminal / Ubiquinol-cytochrome c reductase 8 kDa, N-terminal / Globular protein, non-globular alpha/beta subunit / Cytochrome b-c1 complex, subunit 6 / Cytochrome b-c1 complex subunit 8 / UcrQ family / Cytochrome bc1 complex subunit Rieske, transmembrane domain superfamily ...Cytochrome b-c1 complex subunit 10 / Single alpha-helix domain superfamily / Ubiquinol-cytochrome C reductase complex, 6.4kD protein / Ubiquinol-cytochrome c reductase 8kDa, N-terminal / Ubiquinol-cytochrome c reductase 8 kDa, N-terminal / Globular protein, non-globular alpha/beta subunit / Cytochrome b-c1 complex, subunit 6 / 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] iron-sulphur domain / Rieske [2Fe-2S] 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
FE2/S2 (INORGANIC) CLUSTER / HEME C / PROTOPORPHYRIN IX CONTAINING FE / Chem-JHB / 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 10 ...FE2/S2 (INORGANIC) CLUSTER / HEME C / PROTOPORPHYRIN IX CONTAINING FE / Chem-JHB / 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 10 / 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: 2.88 Å
AuthorsXia, D. / Esser, L. / Zhou, F. / Huang, R.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: J Biol Chem / Year: 2023
Title: Structure of complex III with bound antimalarial agent CK-2-68 provides insights into selective inhibition of Plasmodium cytochrome bc complexes.
Authors: Lothar Esser / Fei Zhou / Allison Zeher / Weimin Wu / Rick Huang / Chang-An Yu / Kristin D Lane / Thomas E Wellems / Di Xia /
Abstract: Among the various components of the protozoan Plasmodium mitochondrial respiratory chain, only Complex III is a validated cellular target for antimalarial drugs. The compound CK-2-68 was developed to ...Among the various components of the protozoan Plasmodium mitochondrial respiratory chain, only Complex III is a validated cellular target for antimalarial drugs. The compound CK-2-68 was developed to specifically target the alternate NADH dehydrogenase of the malaria parasite respiratory chain, but the true target for its antimalarial activity has been controversial. Here, we report the cryo-EM structure of mammalian mitochondrial Complex III bound with CK-2-68 and examine the structure-function relationships of the inhibitor's selective action on Plasmodium. We show that CK-2-68 binds specifically to the quinol oxidation site of Complex III, arresting the motion of the iron-sulfur protein subunit, which suggests an inhibition mechanism similar to that of P-type Complex III inhibitors such as atovaquone, stigmatellin, and UHDBT. Our results shed light on the mechanisms of observed resistance conferred by mutations, elucidate the molecular basis of the wide therapeutic window of CK-2-68 for selective action of Plasmodium vs. host cytochrome bc, and provide guidance for future development of antimalarials targeting Complex III.
History
DepositionFeb 15, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 22, 2023Provider: repository / Type: Initial release
Revision 1.1Sep 6, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
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
E: Cytochrome b-c1 complex subunit Rieske, mitochondrial
F: Cytochrome b-c1 complex subunit 7
G: Cytochrome b-c1 complex subunit 8
H: Cytochrome b-c1 complex subunit 6, mitochondrial
I: Cytochrome b-c1 complex subunit Rieske, mitochondrial
J: Cytochrome b-c1 complex subunit 9
K: Cytochrome b-c1 complex subunit 10
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
R: Cytochrome b-c1 complex subunit Rieske, mitochondrial
S: Cytochrome b-c1 complex subunit 7
T: Cytochrome b-c1 complex subunit 8
U: Cytochrome b-c1 complex subunit 6, mitochondrial
V: Cytochrome b-c1 complex subunit Rieske, mitochondrial
W: Cytochrome b-c1 complex subunit 9
X: Cytochrome b-c1 complex subunit 10
hetero molecules


Theoretical massNumber of molelcules
Total (without water)487,47132
Polymers482,52922
Non-polymers4,94210
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: native gel electrophoresis
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Cytochrome b-c1 complex subunit ... , 9 types, 18 molecules ANBOERFSGTHUIVJWKX

#1: Protein Cytochrome b-c1 complex subunit 1, mitochondrial / Complex III subunit 1 / Core protein I / Ubiquinol-cytochrome-c reductase complex core protein 1


Mass: 49266.254 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / References: UniProt: P31800
#2: Protein Cytochrome b-c1 complex subunit 2, mitochondrial / Complex III subunit 2 / Core protein II / Ubiquinol-cytochrome-c reductase complex core protein 2


Mass: 46575.469 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / References: UniProt: P23004
#5: 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 / Ubiquinol-cytochrome c reductase iron-sulfur subunit


Mass: 21640.580 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / References: UniProt: P13272, quinol-cytochrome-c reductase
#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: 13370.206 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: 9448.833 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: 9189.116 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 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: 7964.259 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / References: UniProt: P13272, quinol-cytochrome-c reductase
#10: 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: 7338.425 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / References: UniProt: P00130
#11: Protein Cytochrome b-c1 complex subunit 10 / Complex III subunit 10 / Complex III subunit XI / Ubiquinol-cytochrome c reductase complex 6.4 kDa protein


Mass: 6527.604 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / References: UniProt: P07552

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Protein , 2 types, 4 molecules CPDQ

#3: 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
#4: 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: 27323.277 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 , 4 types, 10 molecules

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


Mass: 616.487 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#13: Chemical ChemComp-JHB / 7-chloranyl-3-methyl-2-[4-[[4-(trifluoromethyloxy)phenyl]methyl]phenyl]-1~{H}-quinolin-4-one


Mass: 443.845 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H17ClF3NO2 / Feature type: SUBJECT OF INVESTIGATION
#14: Chemical ChemComp-HEC / HEME C


Mass: 618.503 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H34FeN4O4
#15: Chemical ChemComp-FES / FE2/S2 (INORGANIC) CLUSTER


Mass: 175.820 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Fe2S2

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Details

Has ligand of interestY

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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: Bovine heart mitochondrial cytochrome bc1 complex / Type: COMPLEX / Entity ID: #1-#11 / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Bos taurus (cattle)
Buffer solutionpH: 7.5
Buffer componentConc.: 50 mM / Name: TrisCl
SpecimenConc.: 0.3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 277 K

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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: 29000 X / Calibrated magnification: 58275 X / Nominal defocus max: 2600 nm / Nominal defocus min: 700 nm / Calibrated defocus min: 630 nm / Calibrated defocus max: 2820 nm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 80 K / Temperature (min): 80 K
Image recordingElectron dose: 50.24 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 6960

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.20.1_4487refinement
PHENIX1.20.1_4487refinement
EM software
IDNameVersionCategoryDetails
1cisTEM1particle selectionbeta
2SerialEM3.8image acquisition
4cisTEM1CTF correctionbeta
10cisTEM1initial Euler assignmentbeta
11cisTEM1final Euler assignmentbeta
12cisTEM1classificationbeta
13cisTEM13D reconstructionbeta
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 883119
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.88 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 454182 / Num. of class averages: 1 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 72.3 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.005233586
ELECTRON MICROSCOPYf_angle_d0.768745694
ELECTRON MICROSCOPYf_chiral_restr0.04464992
ELECTRON MICROSCOPYf_plane_restr0.00595834
ELECTRON MICROSCOPYf_dihedral_angle_d12.082712136

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