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- PDB-9g9t: Cryo-EM structure of the Toxoplasma gondii respiratory chain comp... -

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Basic information

Entry
Database: PDB / ID: 9g9t
TitleCryo-EM structure of the Toxoplasma gondii respiratory chain complex III inhibited by ELQ-300
Components
  • (Transmembrane ...) x 3
  • (Ubiquinol-cytochrome ...) x 2
  • Alpha-MPP
  • Cytochrome b
  • Cytochrome c1, heme protein
  • Putative peptidase M16 family protein
  • Putative ubiquinol cytochrome c oxidoreductase
  • Putative ubiquinol-cytochrome c reductase hinge protein
  • QCR8/TGGT1_227910
KeywordsELECTRON TRANSPORT / cytochrome bc1 complex / complex III / respiratory chain
Function / homology
Function and homology information


quinol-cytochrome-c reductase / mitochondrial processing peptidase / respiratory chain complex III / quinol-cytochrome-c reductase activity / mitochondrial electron transport, ubiquinol to cytochrome c / metalloendopeptidase activity / 2 iron, 2 sulfur cluster binding / electron transfer activity / mitochondrial inner membrane / heme binding ...quinol-cytochrome-c reductase / mitochondrial processing peptidase / respiratory chain complex III / quinol-cytochrome-c reductase activity / mitochondrial electron transport, ubiquinol to cytochrome c / metalloendopeptidase activity / 2 iron, 2 sulfur cluster binding / electron transfer activity / mitochondrial inner membrane / heme binding / mitochondrion / proteolysis / metal ion binding / membrane
Similarity search - Function
Cytochrome b-c1 complex, subunit 6 / 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 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 ...Cytochrome b-c1 complex, subunit 6 / 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 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 / : / 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 family profile. / Cytochrome c-like domain / Cytochrome c-like domain superfamily
Similarity search - Domain/homology
: / CARDIOLIPIN / HEME C / PROTOPORPHYRIN IX CONTAINING FE / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / Putative peptidase M16, alpha subunit / Uncharacterized protein / Ubiquinol-cytochrome c reductase / Transmembrane protein / Cytochrome b ...: / CARDIOLIPIN / HEME C / PROTOPORPHYRIN IX CONTAINING FE / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / Putative peptidase M16, alpha subunit / Uncharacterized protein / Ubiquinol-cytochrome c reductase / Transmembrane protein / Cytochrome b / Putative ubiquinol cytochrome c oxidoreductase / Transmembrane protein / Transmembrane protein / Ubiquinol-cytochrome C family reductase UQCRX/QCR9-like protein / Putative ubiquinol-cytochrome c reductase hinge protein / Putative peptidase M16 family potein / Cytochrome c1, heme protein
Similarity search - Component
Biological speciesToxoplasma gondii (eukaryote)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 1.8 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
DepositionJul 25, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 18, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cytochrome b
B: Cytochrome c1, heme protein
C: Putative ubiquinol cytochrome c oxidoreductase
D: Putative peptidase M16 family protein
E: Alpha-MPP
F: Putative ubiquinol-cytochrome c reductase hinge protein
G: Ubiquinol-cytochrome c reductase
H: QCR8/TGGT1_227910
I: Ubiquinol-cytochrome C family reductase UQCRX/QCR9-like protein
J: Transmembrane protein
K: Transmembrane protein
L: Transmembrane protein
a: Cytochrome b
b: Cytochrome c1, heme protein
c: Putative ubiquinol cytochrome c oxidoreductase
d: Putative peptidase M16 family protein
e: Alpha-MPP
f: Putative ubiquinol-cytochrome c reductase hinge protein
g: Ubiquinol-cytochrome c reductase
h: QCR8/TGGT1_227910
i: Ubiquinol-cytochrome C family reductase UQCRX/QCR9-like protein
j: Transmembrane protein
k: Transmembrane protein
l: Transmembrane protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)759,41756
Polymers728,62724
Non-polymers30,79132
Water12,304683
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 , 7 types, 14 molecules AaBbCcDdEeFfHh

#1: 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: 40794.430 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Toxoplasma gondii (eukaryote) / Gene: MT-CYB, COB, CYTB, MTCYB / Production host: Toxoplasma gondii (eukaryote) / References: UniProt: O20672
#2: Protein Cytochrome c1, heme protein


Mass: 46025.355 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Toxoplasma gondii (eukaryote) / Gene: TGGT1_246540 / Production host: Toxoplasma gondii (eukaryote) / References: UniProt: S7W9J5
#3: Protein Putative ubiquinol cytochrome c oxidoreductase


Mass: 54869.145 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Toxoplasma gondii (eukaryote) / Gene: TGGT1_320220 / Production host: Toxoplasma gondii (eukaryote) / References: UniProt: S7UK06, quinol-cytochrome-c reductase
#4: Protein Putative peptidase M16 family protein


Mass: 56986.824 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Putative peptidase M16 family protein / Source: (gene. exp.) Toxoplasma gondii (eukaryote) / Gene: TGGT1_236210 / Production host: Toxoplasma gondii (eukaryote)
References: UniProt: S7W617, mitochondrial processing peptidase
#5: Protein Alpha-MPP


Mass: 62238.395 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Toxoplasma gondii (eukaryote) / Gene: TGGT1_202680 / Production host: Toxoplasma gondii (eukaryote) / References: UniProt: A0A125YN38
#6: Protein Putative ubiquinol-cytochrome c reductase hinge protein


Mass: 10509.094 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Toxoplasma gondii (eukaryote) / Gene: TGGT1_320140 / Production host: Toxoplasma gondii (eukaryote) / References: UniProt: S7VSS5
#8: Protein QCR8/TGGT1_227910


Mass: 14391.657 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Toxoplasma gondii (eukaryote) / Gene: TGGT1_227910 / Production host: Toxoplasma gondii (eukaryote) / References: UniProt: A0A125YW19

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Ubiquinol-cytochrome ... , 2 types, 4 molecules GgIi

#7: Protein Ubiquinol-cytochrome c reductase


Mass: 26777.564 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Toxoplasma gondii (eukaryote) / Gene: TGGT1_288750 / Production host: Toxoplasma gondii (eukaryote) / References: UniProt: A0A125YYJ3
#9: Protein Ubiquinol-cytochrome C family reductase UQCRX/QCR9-like protein


Mass: 15290.577 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Toxoplasma gondii (eukaryote) / Gene: TGGT1_201880 / Production host: Toxoplasma gondii (eukaryote) / References: UniProt: S7UVH4

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Transmembrane ... , 3 types, 6 molecules JjKkLl

#10: Protein Transmembrane protein


Mass: 9455.947 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Toxoplasma gondii (eukaryote) / Gene: TGGT1_214250 / Production host: Toxoplasma gondii (eukaryote) / References: UniProt: S7UR33
#11: Protein Transmembrane protein


Mass: 15250.601 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Toxoplasma gondii (eukaryote) / Gene: TGGT1_207170 / Production host: Toxoplasma gondii (eukaryote) / References: UniProt: A0A125YZN9
#12: Protein Transmembrane protein


Mass: 11723.664 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Toxoplasma gondii (eukaryote) / Gene: TGGT1_312940 / Production host: Toxoplasma gondii (eukaryote) / References: UniProt: S7UTB5

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Non-polymers , 8 types, 715 molecules

#13: 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.: 16 / Source method: obtained synthetically / Formula: C81H156O17P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: phospholipid*YM
#14: Chemical
ChemComp-A1IJD / 6-chloranyl-7-methoxy-2-methyl-3-[4-[4-(trifluoromethyloxy)phenoxy]phenyl]-1~{H}-quinolin-4-one


Mass: 475.844 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H17ClF3NO4
#15: 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
#16: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: Mg
#17: Chemical ChemComp-HEC / HEME C


Mass: 618.503 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H34FeN4O4 / Feature type: SUBJECT OF INVESTIGATION
#18: 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
#19: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#20: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 683 / 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: Cytochrome bc1 complex from Toxoplasma gondii / Type: COMPLEX / Entity ID: #1-#12 / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Toxoplasma gondii (eukaryote) / Strain: RH
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE / Humidity: 100 %

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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: 1400 nm / Nominal defocus min: 400 nm / C2 aperture diameter: 2.7 µm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 36 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.21.1_5286: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 1.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 2056878 / Algorithm: FOURIER SPACE / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00442126
ELECTRON MICROSCOPYf_angle_d0.55357000
ELECTRON MICROSCOPYf_dihedral_angle_d12.11315974
ELECTRON MICROSCOPYf_chiral_restr0.0415844
ELECTRON MICROSCOPYf_plane_restr0.0067110

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