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- PDB-8zow: Cryo-EM structure of Metyltetraprole-bound porcine bc1 complex -

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Basic information

Entry
Database: PDB / ID: 8zow
TitleCryo-EM structure of Metyltetraprole-bound porcine bc1 complex
Components
  • (Cytochrome b-c1 complex subunit ...) x 8
  • Complex III subunit 9
  • Cytochrome b
  • Cytochrome c1, heme protein, mitochondrial
KeywordsPROTEIN BINDING / Metyltetraprole / Inhibitor / Complex
Function / homology
Function and homology information


Complex III assembly / subthalamus development / pons development / cerebellar Purkinje cell layer development / pyramidal neuron development / thalamus development / Respiratory electron transport / Mitochondrial protein degradation / respiratory chain complex III / quinol-cytochrome-c reductase ...Complex III assembly / subthalamus development / pons development / cerebellar Purkinje cell layer development / pyramidal neuron development / thalamus development / Respiratory electron transport / Mitochondrial protein degradation / respiratory chain complex III / quinol-cytochrome-c reductase / ubiquinol-cytochrome-c reductase activity / midbrain development / hypothalamus development / mitochondrial electron transport, ubiquinol to cytochrome c / hippocampus development / metalloendopeptidase activity / 2 iron, 2 sulfur cluster binding / electron transfer activity / mitochondrial inner membrane / heme binding / mitochondrion / proteolysis / membrane / metal ion binding
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 / 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 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 / 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 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. / 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
: / CARDIOLIPIN / FE2/S2 (INORGANIC) CLUSTER / HEME C / PROTOPORPHYRIN IX CONTAINING FE / 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / Cytochrome b-c1 complex subunit 7 / Cytochrome b-c1 complex subunit Rieske, mitochondrial / Cytochrome b-c1 complex subunit Rieske, mitochondrial / Cytochrome c1, heme protein, mitochondrial ...: / CARDIOLIPIN / FE2/S2 (INORGANIC) CLUSTER / HEME C / PROTOPORPHYRIN IX CONTAINING FE / 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / Cytochrome b-c1 complex subunit 7 / Cytochrome b-c1 complex subunit Rieske, mitochondrial / Cytochrome b-c1 complex subunit Rieske, mitochondrial / Cytochrome c1, heme protein, mitochondrial / Cytochrome b-c1 complex subunit 8 / Cytochrome b-c1 complex subunit 2, mitochondrial / Cytochrome b-c1 complex subunit 1, mitochondrial / Complex III subunit 9 / Cytochrome b-c1 complex subunit 6 / Cytochrome b-c1 complex subunit 10 / Cytochrome b
Similarity search - Component
Biological speciesSus scrofa (pig)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.53 Å
AuthorsWang, Y.X. / Sun, J.Y. / Cui, G.R. / Yang, G.F.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: J Am Chem Soc / Year: 2024
Title: Cryo-EM Structures Reveal the Unique Binding Modes of Metyltetraprole in Yeast and Porcine Cytochrome Complex Enabling Rational Design of Inhibitors.
Authors: Yu-Xia Wang / Ying Ye / Zhi-Wen Li / Guang-Rui Cui / Xing-Xing Shi / Ying Dong / Jia-Jia Jiang / Jia-Yue Sun / Ze-Wei Guan / Nan Zhang / Qiong-You Wu / Fan Wang / Xiao-Lei Zhu / Guang-Fu Yang /
Abstract: Cytochrome (complex III) represents a significant target for the discovery of both drugs and fungicides. Metyltetraprole (MET) is commonly classified as a quinone site inhibitor (QI) that combats ...Cytochrome (complex III) represents a significant target for the discovery of both drugs and fungicides. Metyltetraprole (MET) is commonly classified as a quinone site inhibitor (QI) that combats the G143A mutated isolate, which confers high resistance to strobilurin fungicides such as pyraclostrobin (PYR). The binding mode and antiresistance mechanism of MET remain unclear. Here, we determined the high-resolution structures of inhibitor-bound complex III (MET, 2.52 Å; PYR, 2.42 Å) and inhibitor-bound porcine complex III (MET, 2.53 Å; PYR, 2,37 Å) by cryo-electron microscopy. The distinct binding modes of MET and PYR were observed for the first time. Notably, the MET exhibited different binding modes in the two species. In , the binding site of MET was the same as PYR, serving as a -type inhibitor of the Q site. However, in porcine, MET acted as a dual-target inhibitor of both Q and Q. Based on the structural insights, a novel inhibitor (YF23694) was discovered and demonstrated excellent fungicidal activity against downy mildew and powdery mildew fungi. This work provides a new starting point for the design of the next generation of inhibitors to overcome the resistance.
History
DepositionMay 29, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Dec 25, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Cytochrome b
B: Cytochrome c1, heme protein, mitochondrial
C: Cytochrome b-c1 complex subunit Rieske, mitochondrial
D: Cytochrome b-c1 complex subunit 1, mitochondrial
E: Cytochrome b-c1 complex subunit 2, mitochondrial
F: Cytochrome b-c1 complex subunit 6
G: Cytochrome b-c1 complex subunit 7
H: Cytochrome b-c1 complex subunit 8
I: Complex III subunit 9
J: Cytochrome b-c1 complex subunit 10
K: Cytochrome b-c1 complex subunit Rieske, mitochondrial
a: Cytochrome b
b: Cytochrome c1, heme protein, mitochondrial
c: Cytochrome b-c1 complex subunit Rieske, mitochondrial
d: Cytochrome b-c1 complex subunit 1, mitochondrial
e: Cytochrome b-c1 complex subunit 2, mitochondrial
f: Cytochrome b-c1 complex subunit 6
g: Cytochrome b-c1 complex subunit 7
h: Cytochrome b-c1 complex subunit 8
i: Complex III subunit 9
j: Cytochrome b-c1 complex subunit 10
k: Cytochrome b-c1 complex subunit Rieske, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)479,31038
Polymers469,25222
Non-polymers10,05816
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 3 types, 6 molecules AaBbIi

#1: Protein Cytochrome b


Mass: 42709.520 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Sus scrofa (pig) / References: UniProt: Q1HBG9
#2: Protein Cytochrome c1, heme protein, mitochondrial


Mass: 27373.357 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Sus scrofa (pig) / References: UniProt: A0A4X1UNI7
#9: Protein Complex III subunit 9


Mass: 7152.220 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Sus scrofa (pig) / References: UniProt: A0A8D1J3N6

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Cytochrome b-c1 complex subunit ... , 8 types, 16 molecules CcDdEeFfGgHhJjKk

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


Mass: 21610.492 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Sus scrofa (pig)
References: UniProt: A0A4X1TWD8, quinol-cytochrome-c reductase
#4: Protein Cytochrome b-c1 complex subunit 1, mitochondrial


Mass: 49270.133 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Sus scrofa (pig) / References: UniProt: A0A8D0PK14
#5: Protein Cytochrome b-c1 complex subunit 2, mitochondrial


Mass: 44616.098 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Sus scrofa (pig) / References: UniProt: A0A4X1V0F2
#6: Protein Cytochrome b-c1 complex subunit 6


Mass: 7592.541 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Sus scrofa (pig) / References: UniProt: F1S3W0
#7: Protein Cytochrome b-c1 complex subunit 7


Mass: 13043.888 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Sus scrofa (pig) / References: UniProt: A0A286ZPR8
#8: Protein Cytochrome b-c1 complex subunit 8 / Complex III subunit 8


Mass: 9408.876 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Sus scrofa (pig) / References: UniProt: A0A4X1UYT9
#10: Protein Cytochrome b-c1 complex subunit 10 / Ubiquinol-cytochrome c reductase / complex III subunit XI


Mass: 6058.093 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Sus scrofa (pig) / References: UniProt: F1SDI2
#11: Protein Cytochrome b-c1 complex subunit Rieske, mitochondrial


Mass: 5790.676 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Sus scrofa (pig)
References: UniProt: A0A480EHC1, quinol-cytochrome-c reductase

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Non-polymers , 6 types, 16 molecules

#12: Chemical
ChemComp-A1D6P / 1-[2-[[1-(4-chlorophenyl)pyrazol-3-yl]oxymethyl]-3-methyl-phenyl]-4-methyl-1,2,3,4-tetrazol-5-one / Metyltetraprole


Mass: 396.830 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H17ClN6O2 / Feature type: SUBJECT OF INVESTIGATION
#13: Chemical
ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#14: Chemical ChemComp-PEE / 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / DOPE


Mass: 744.034 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C41H78NO8P / Comment: DOPE, phospholipid*YM
#15: 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.: 2 / Source method: obtained synthetically / Formula: C81H156O17P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: phospholipid*YM
#16: Chemical ChemComp-HEC / HEME C


Mass: 618.503 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H34FeN4O4
#17: 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
Has protein modificationN

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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: Cryo-EM structure of Metyltetraprole-bound porcine bc1 complex
Type: COMPLEX / Entity ID: #1-#11 / Source: NATURAL
Source (natural)Organism: Sus scrofa (pig)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
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 FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 1600 nm
Image recordingElectron dose: 49.72 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.53 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 411418 / Symmetry type: POINT

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