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- PDB-9h8t: Cryo-EM structure of the atovaquone-inhibited Complex III from th... -

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Basic information

Entry
Database: PDB / ID: 9h8t
TitleCryo-EM structure of the atovaquone-inhibited Complex III from the Chlorocebus sabaeus respirasome
Components
  • (Cytochrome b-c1 complex subunit ...) x 4
  • (Ubiquinol-cytochrome c reductase core protein ...) x 2
  • Complex III subunit 9
  • Cytochrome b
  • Cytochrome c1
  • UQCRB
KeywordsELECTRON TRANSPORT / complex III / respirasome / mitochondria / green african monkey / atovaquone
Function / homology
Function and homology information


subthalamus development / pons development / cerebellar Purkinje cell layer development / pyramidal neuron development / thalamus development / mitochondrial respiratory chain complex III assembly / respiratory chain complex III / quinol-cytochrome-c reductase / quinol-cytochrome-c reductase activity / mitochondrial electron transport, ubiquinol to cytochrome c ...subthalamus development / pons development / cerebellar Purkinje cell layer development / pyramidal neuron development / thalamus development / mitochondrial respiratory chain complex III assembly / respiratory chain complex III / quinol-cytochrome-c reductase / quinol-cytochrome-c reductase activity / mitochondrial electron transport, ubiquinol to cytochrome c / hypothalamus development / midbrain development / hippocampus development / respiratory electron transport chain / metalloendopeptidase activity / 2 iron, 2 sulfur cluster binding / electron transfer activity / mitochondrial inner membrane / heme binding / proteolysis / nucleoplasm / metal ion binding
Similarity search - Function
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 ...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 8 superfamily / Cytochrome b-c1 complex subunit Rieske, transmembrane domain / Ubiquinol cytochrome reductase transmembrane region / Cytochrome b-c1 complex subunit 9 / Cytochrome b-c1 complex subunit 9 superfamily / Ubiquinol-cytochrome C reductase, UQCRX/QCR9 like / 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. / Peptidase M16, zinc-binding site / Insulinase family, zinc-binding region signature. / Cytochrome b/b6, C-terminal domain superfamily / Cytochrome b/b6/petB / 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-like domain superfamily
Similarity search - Domain/homology
Chem-AFI / Chem-AOQ / CARDIOLIPIN / FE2/S2 (INORGANIC) CLUSTER / HEME C / PROTOPORPHYRIN IX CONTAINING FE / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / Cytochrome b-c1 complex subunit Rieske, mitochondrial / Cytochrome b-c1 complex subunit 2, mitochondrial ...Chem-AFI / Chem-AOQ / CARDIOLIPIN / FE2/S2 (INORGANIC) CLUSTER / HEME C / PROTOPORPHYRIN IX CONTAINING FE / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / Cytochrome b-c1 complex subunit Rieske, mitochondrial / Cytochrome b-c1 complex subunit 2, mitochondrial / Cytochrome c1, heme protein, mitochondrial / Complex III subunit 9 / Cytochrome b-c1 complex subunit 7 / Cytochrome b-c1 complex subunit 8 / Cytochrome b-c1 complex subunit 6 / Cytochrome b
Similarity search - Component
Biological speciesChlorocebus sabaeus (green monkey)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.67 Å
AuthorsMaclean, A. / Muhleip, A.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome Trust United Kingdom
CitationJournal: Nat Struct Mol Biol / Year: 2025
Title: Structure, assembly and inhibition of the Toxoplasma gondii respiratory chain supercomplex.
Authors: Andrew E MacLean / Shikha Shikha / Mariana Ferreira Silva / Max J Gramelspacher / Aaron Nilsen / Katherine M Liebman / Sovitj Pou / Rolf W Winter / Amit Meir / Michael K Riscoe / J Stone ...Authors: Andrew E MacLean / Shikha Shikha / Mariana Ferreira Silva / Max J Gramelspacher / Aaron Nilsen / Katherine M Liebman / Sovitj Pou / Rolf W Winter / Amit Meir / Michael K Riscoe / J Stone Doggett / Lilach Sheiner / Alexander Mühleip /
Abstract: The apicomplexan mitochondrial electron transport chain is essential for parasite survival and displays a divergent subunit composition. Here we report cryo-electron microscopy structures of an ...The apicomplexan mitochondrial electron transport chain is essential for parasite survival and displays a divergent subunit composition. Here we report cryo-electron microscopy structures of an apicomplexan III-IV supercomplex and of the drug target complex III. The supercomplex structure reveals how clade-specific subunits form an apicomplexan-conserved III-IV interface with a unique, kinked architecture, suggesting that supercomplexes evolved independently in different eukaryotic lineages. A knockout resulting in supercomplex disassembly challenges the proposed role of III-IV in electron transfer efficiency as suggested for mammals. Nevertheless, knockout analysis indicates that III-IV is critical for parasite fitness. The complexes from the model parasite Toxoplasma gondii were inhibited with the antimalarial atovaquone, revealing interactions underpinning species specificity. They were also inhibited with endochin-like quinolone (ELQ)-300, an inhibitor in late-stage preclinical development. Notably, in the apicomplexan binding site, ELQ-300 is flipped compared with related compounds in the mammalian enzyme. On the basis of the binding modes and parasite-specific interactions discovered, we designed more potent ELQs with subnanomolar activity against T. gondii. Our findings reveal critical evolutionary differences in the role of supercomplexes in mitochondrial biology and provide insight into cytochrome b inhibition, informing future drug discovery.
History
DepositionOct 29, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 2, 2025Provider: repository / Type: Initial release
Revision 1.0Jul 2, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 2, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jul 2, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 2, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 2, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 2, 2025Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Jul 2, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
D: Cytochrome c1
A: Cytochrome b-c1 complex subunit Rieske, mitochondrial
G: Cytochrome b-c1 complex subunit 7
C: Cytochrome b-c1 complex subunit 8
E: Complex III subunit 9
F: Cytochrome b-c1 complex subunit 6
K: Ubiquinol-cytochrome c reductase core protein 2
J: Cytochrome b
L: Ubiquinol-cytochrome c reductase core protein 1
H: UQCRB
T: Cytochrome b-c1 complex subunit Rieske, mitochondrial
d: Cytochrome c1
a: Cytochrome b-c1 complex subunit Rieske, mitochondrial
g: Cytochrome b-c1 complex subunit 7
c: Cytochrome b-c1 complex subunit 8
e: Complex III subunit 9
f: Cytochrome b-c1 complex subunit 6
k: Ubiquinol-cytochrome c reductase core protein 2
j: Cytochrome b
l: Ubiquinol-cytochrome c reductase core protein 1
h: UQCRB
hetero molecules


Theoretical massNumber of molelcules
Total (without water)562,71547
Polymers545,16221
Non-polymers17,55326
Water25214
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 4 types, 8 molecules DdEeJjHh

#1: Protein Cytochrome c1


Mass: 35268.703 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Chlorocebus sabaeus (green monkey) / References: UniProt: A0A0D9R8S7
#5: Protein Complex III subunit 9


Mass: 7320.473 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Chlorocebus sabaeus (green monkey) / References: UniProt: A0A0D9RB67
#8: Protein Cytochrome b


Mass: 43070.770 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Chlorocebus sabaeus (green monkey) / References: UniProt: Q1AL63
#10: Protein UQCRB


Mass: 6623.710 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Chlorocebus sabaeus (green monkey) / Production host: Chlorocebus sabaeus (green monkey)

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Cytochrome b-c1 complex subunit ... , 4 types, 9 molecules ATaGgCcFf

#2: Protein Cytochrome b-c1 complex subunit Rieske, mitochondrial


Mass: 29817.166 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Source: (natural) Chlorocebus sabaeus (green monkey)
References: UniProt: A0A0D9QXW2, quinol-cytochrome-c reductase
#3: Protein Cytochrome b-c1 complex subunit 7


Mass: 13540.450 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Chlorocebus sabaeus (green monkey) / References: UniProt: A0A0D9RJ49
#4: Protein Cytochrome b-c1 complex subunit 8 / Complex III subunit 8


Mass: 9748.262 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Chlorocebus sabaeus (green monkey) / References: UniProt: A0A0D9RML3
#6: Protein Cytochrome b-c1 complex subunit 6


Mass: 10803.954 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Chlorocebus sabaeus (green monkey) / References: UniProt: A0A0D9S9I7

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Ubiquinol-cytochrome c reductase core protein ... , 2 types, 4 molecules KkLl

#7: Protein Ubiquinol-cytochrome c reductase core protein 2


Mass: 48592.984 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Chlorocebus sabaeus (green monkey) / References: UniProt: A0A0D9R493
#9: Protein Ubiquinol-cytochrome c reductase core protein 1


Mass: 52885.816 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Chlorocebus sabaeus (green monkey)

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Non-polymers , 10 types, 40 molecules

#11: Chemical ChemComp-HEC / HEME C


Mass: 618.503 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H34FeN4O4 / Feature type: SUBJECT OF INVESTIGATION
#12: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#13: Chemical ChemComp-FES / FE2/S2 (INORGANIC) CLUSTER


Mass: 175.820 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Fe2S2 / Feature type: SUBJECT OF INVESTIGATION
#14: Chemical
ChemComp-CDL / CARDIOLIPIN / DIPHOSPHATIDYL GLYCEROL / BIS-(1,2-DIACYL-SN-GLYCERO-3-PHOSPHO)-1',3'-SN-GLYCEROL


Mass: 1464.043 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C81H156O17P2 / Comment: phospholipid*YM
#15: Chemical ChemComp-PC1 / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / 3-SN-PHOSPHATIDYLCHOLINE


Mass: 790.145 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C44H88NO8P / Comment: phospholipid*YM
#16: Chemical ChemComp-AOQ / 2-[trans-4-(4-chlorophenyl)cyclohexyl]-3-hydroxynaphthalene-1,4-dione / Atovaquone


Mass: 366.837 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H19ClO3 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, Antimicrobial*YM
#17: Chemical
ChemComp-PEE / 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / DOPE


Mass: 744.034 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C41H78NO8P / Comment: DOPE, phospholipid*YM
#18: Chemical ChemComp-AFI / 2-[4-(4-CHLOROPHENYL)CYCLOHEXYLIDENE]-3,4-DIHYDROXY-1(2H)-NAPHTHALENONE


Mass: 366.837 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H19ClO3 / Feature type: SUBJECT OF INVESTIGATION
#19: Chemical
ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H32FeN4O4 / Feature type: SUBJECT OF INVESTIGATION
#20: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 14 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
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: mitochondrial respirasome from Chlorocebus sabaeus Vero cells inhibited by atovaquone
Type: COMPLEX / Entity ID: #1-#10 / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Chlorocebus sabaeus (green monkey) / Strain: Vero cell line
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 301 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 defocus max: 1600 nm / Nominal defocus min: 600 nm / Cs: 2.7 mm
Image recordingElectron dose: 36 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.67 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 637526 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00534366
ELECTRON MICROSCOPYf_angle_d0.90746568
ELECTRON MICROSCOPYf_dihedral_angle_d13.88312820
ELECTRON MICROSCOPYf_chiral_restr0.055024
ELECTRON MICROSCOPYf_plane_restr0.0145897

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