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- PDB-8hcr: Cryo-EM structure of the Mycobacterium tuberculosis cytochrome bc... -

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Basic information

Entry
Database: PDB / ID: 8hcr
TitleCryo-EM structure of the Mycobacterium tuberculosis cytochrome bcc:aa3 supercomplex and a novel inhibitor targeting subunit cytochrome cI
Components
  • (CYTOCHROME AA3 SUBUNIT ...) x 2
  • (Cytochrome bc1 complex cytochrome ...) x 2
  • (Probable cytochrome c oxidase subunit ...) x 2
  • Cytochrome bc1 complex Rieske iron-sulfur subunit
  • Cytochrome c oxidase polypeptide 4
  • DUF5130 domain-containing protein
KeywordsOXIDOREDUCTASE / Cytochrome bcc:aa3 oxidase / Mycobacterium tuberculosis
Function / homology
Function and homology information


oxidoreduction-driven active transmembrane transporter activity / aerobic electron transport chain / cytochrome-c oxidase / quinol-cytochrome-c reductase / ubiquinol-cytochrome-c reductase activity / oxidative phosphorylation / electron transport coupled proton transport / cytochrome-c oxidase activity / oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen / respirasome ...oxidoreduction-driven active transmembrane transporter activity / aerobic electron transport chain / cytochrome-c oxidase / quinol-cytochrome-c reductase / ubiquinol-cytochrome-c reductase activity / oxidative phosphorylation / electron transport coupled proton transport / cytochrome-c oxidase activity / oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen / respirasome / aerobic respiration / respiratory electron transport chain / monooxygenase activity / 2 iron, 2 sulfur cluster binding / electron transfer activity / iron ion binding / heme binding / membrane / metal ion binding / plasma membrane
Similarity search - Function
Protein of unknown function DUF5130 / Domain of unknown function (DUF5130) / QcrA subunit, N-terminal / QcrA subunit N-terminal region / Cytochrome bc1 complex, cytochrome c subunit / Cytochrome c oxidase subunit IV, actinobacteria / Cytochrome c oxidase subunit IV / Cytochrome b(N-terminal)/b6/petB / Cytochrome c oxidase, subunit I bacterial type / Cytochrome C oxidase, cbb3-type, subunit III ...Protein of unknown function DUF5130 / Domain of unknown function (DUF5130) / QcrA subunit, N-terminal / QcrA subunit N-terminal region / Cytochrome bc1 complex, cytochrome c subunit / Cytochrome c oxidase subunit IV, actinobacteria / Cytochrome c oxidase subunit IV / Cytochrome b(N-terminal)/b6/petB / Cytochrome c oxidase, subunit I bacterial type / Cytochrome C oxidase, cbb3-type, subunit III / Cytochrome c oxidase subunit III / Cytochrome c oxidase subunit III-like / Cytochrome c oxidase, subunit III, 4-helical bundle / Cytochrome c oxidase subunit III / Heme-copper oxidase subunit III family profile. / Cytochrome c oxidase subunit III-like superfamily / Cytochrome c oxidase, subunit I, copper-binding site / Heme-copper oxidase catalytic subunit, copper B binding region signature. / Cytochrome c oxidase-like, subunit I domain / Cytochrome oxidase subunit I profile. / Cytochrome b/b6, N-terminal / Cytochrome b/b6-like domain superfamily / Cytochrome b/b6 N-terminal region profile. / Cytochrome c oxidase subunit I / Cytochrome c oxidase-like, subunit I superfamily / Cytochrome C and Quinol oxidase polypeptide I / Di-haem cytochrome, transmembrane / Rieske iron-sulphur protein / Cytochrome c / 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-A / HEME C / PROTOPORPHYRIN IX CONTAINING FE / Cytochrome bc1 complex Rieske iron-sulfur subunit / Cytochrome c oxidase polypeptide 4 / Cytochrome bc1 complex cytochrome b subunit / DUF5130 domain-containing protein / Cytochrome bc1 complex cytochrome c subunit / Probable cytochrome c oxidase subunit 3 / Probable cytochrome c oxidase subunit 1
Similarity search - Component
Biological speciesMycobacterium tuberculosis variant bovis BCG (bacteria)
MethodELECTRON MICROSCOPY / electron tomography / cryo EM
AuthorsMathiyazakan, V. / Gruber, G.
Funding support Singapore, 1items
OrganizationGrant numberCountry
National Research Foundation (NRF, Singapore)NRF-CRP18-2017-01 Singapore
CitationJournal: Antimicrob Agents Chemother / Year: 2023
Title: Cryo-Electron Microscopy Structure of the s Cytochrome : Supercomplex and a Novel Inhibitor Targeting Subunit Cytochrome I.
Authors: Vikneswaran Mathiyazakan / Chui-Fann Wong / Amaravadhi Harikishore / Kevin Pethe / Gerhard Grüber /
Abstract: The mycobacterial cytochrome complex deserves the name "supercomplex" since it combines three cytochrome oxidases-cytochrome , cytochrome , and cytochrome -into one supramolecular machine and ...The mycobacterial cytochrome complex deserves the name "supercomplex" since it combines three cytochrome oxidases-cytochrome , cytochrome , and cytochrome -into one supramolecular machine and performs electron transfer for the reduction of oxygen to water and proton transport to generate the proton motive force for ATP synthesis. Thus, the complex represents a valid drug target for Mycobacterium tuberculosis infections. The production and purification of an entire M. tuberculosis cytochrome are fundamental for biochemical and structural characterization of this supercomplex, paving the way for new inhibitor targets and molecules. Here, we produced and purified the entire and active M. tuberculosis cyt- oxidase, as demonstrated by the different heme spectra and an oxygen consumption assay. The resolved M. tuberculosis cyt- cryo-electron microscopy structure reveals a dimer with its functional domains involved in electron, proton, oxygen transfer, and oxygen reduction. The structure shows the two cytochrome III head domains of the dimer, the counterpart of the soluble mitochondrial cytochrome , in a so-called "closed state," in which electrons are translocated from the to the domain. The structural and mechanistic insights provided the basis for a virtual screening campaign that identified a potent M. tuberculosis cyt- inhibitor, cyt1. cyt1 targets the mycobacterium-specific α3-helix of cytochrome I and interferes with oxygen consumption by interrupting electron translocation via the III head. The successful identification of a new cyt- inhibitor demonstrates the potential of a structure-mechanism-based approach for novel compound development.
History
DepositionNov 2, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 3, 2023Provider: repository / Type: Initial release
Revision 1.1May 24, 2023Group: Database references / Category: 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.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Jun 28, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Sep 13, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cytochrome bc1 complex Rieske iron-sulfur subunit
B: Cytochrome bc1 complex cytochrome b subunit
C: Cytochrome bc1 complex cytochrome c subunit
E: CYTOCHROME AA3 SUBUNIT CtaC
F: Probable cytochrome c oxidase subunit 1
G: Probable cytochrome c oxidase subunit 3
H: Cytochrome c oxidase polypeptide 4
I: CYTOCHROME AA3 SUBUNIT CtaJ
J: DUF5130 domain-containing protein
M: Cytochrome bc1 complex Rieske iron-sulfur subunit
N: Cytochrome bc1 complex cytochrome b subunit
O: Cytochrome bc1 complex cytochrome c subunit
Q: CYTOCHROME AA3 SUBUNIT CtaC
R: Probable cytochrome c oxidase subunit 1
S: Probable cytochrome c oxidase subunit 3
T: Cytochrome c oxidase polypeptide 4
U: CYTOCHROME AA3 SUBUNIT CtaJ
V: DUF5130 domain-containing protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)620,76432
Polymers612,06118
Non-polymers8,70314
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 3 types, 6 molecules AMHTJV

#1: Protein Cytochrome bc1 complex Rieske iron-sulfur subunit / Cytochrome bc1 reductase complex subunit QcrA / Rieske iron-sulfur protein


Mass: 46976.465 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis variant bovis BCG (bacteria)
Gene: aioB, qcrA, ERS007663_00404, ERS007670_01335, ERS007679_00448, ERS007681_03213, ERS007703_01913, ERS007720_01586, ERS007722_02477, ERS007741_02707, SAMEA2683035_01305
Production host: Mycobacterium tuberculosis variant bovis BCG (bacteria)
References: UniProt: A0A045GW18
#7: Protein Cytochrome c oxidase polypeptide 4 / Cytochrome aa3 subunit 4 / Cytochrome c oxidase polypeptide IV


Mass: 14874.137 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis variant bovis BCG (bacteria)
Gene: RN06_2699
Production host: Mycobacterium tuberculosis variant bovis BCG (bacteria)
References: UniProt: A0A0K2HXG0, cytochrome-c oxidase
#9: Protein DUF5130 domain-containing protein


Mass: 15982.042 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis variant bovis BCG (bacteria)
Gene: K60_025630
Production host: Mycobacterium tuberculosis variant bovis BCG (bacteria)
References: UniProt: A0A7U4BVZ0

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Cytochrome bc1 complex cytochrome ... , 2 types, 4 molecules BNCO

#2: Protein Cytochrome bc1 complex cytochrome b subunit / Cytochrome bc1 reductase complex subunit QcrB


Mass: 63925.984 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis variant bovis BCG (bacteria)
Gene: RN06_2696
Production host: Mycobacterium tuberculosis variant bovis BCG (bacteria)
References: UniProt: A0A0K2HYC0, quinol-cytochrome-c reductase
#3: Protein Cytochrome bc1 complex cytochrome c subunit / Cytochrome bc1 reductase complex subunit QcrC / Ubiquinol--cytochrome c reductase cytochrome c subunit


Mass: 29170.404 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis variant bovis BCG (bacteria)
Gene: qcrC, Rv2194, MTCY190.05
Production host: Mycobacterium tuberculosis variant bovis BCG (bacteria)
References: UniProt: P9WP35, quinol-cytochrome-c reductase

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CYTOCHROME AA3 SUBUNIT ... , 2 types, 4 molecules EQIU

#4: Protein CYTOCHROME AA3 SUBUNIT CtaC


Mass: 40535.582 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis variant bovis BCG (bacteria)
Production host: Mycobacterium tuberculosis variant bovis BCG (bacteria)
#8: Protein CYTOCHROME AA3 SUBUNIT CtaJ


Mass: 8408.646 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis variant bovis BCG (bacteria)
Production host: Mycobacterium tuberculosis variant bovis BCG (bacteria)

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Probable cytochrome c oxidase subunit ... , 2 types, 4 molecules FRGS

#5: Protein Probable cytochrome c oxidase subunit 1 / Cytochrome aa3 subunit 1 / Cytochrome c oxidase polypeptide I


Mass: 63722.289 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis variant bovis BCG (bacteria)
Gene: ctaD, Rv3043c, MTV012.58c
Production host: Mycobacterium tuberculosis variant bovis BCG (bacteria)
References: UniProt: P9WP71, cytochrome-c oxidase
#6: Protein Probable cytochrome c oxidase subunit 3 / Cytochrome aa3 subunit 3 / Cytochrome c oxidase polypeptide III


Mass: 22435.021 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis variant bovis BCG (bacteria)
Gene: ctaE, Rv2193, MTCY190.04
Production host: Mycobacterium tuberculosis variant bovis BCG (bacteria)
References: UniProt: P9WP67, cytochrome-c oxidase

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Non-polymers , 4 types, 14 molecules

#10: Chemical ChemComp-FES / FE2/S2 (INORGANIC) CLUSTER / Iron–sulfur cluster


Mass: 175.820 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Fe2S2 / Feature type: SUBJECT OF INVESTIGATION
#11: Chemical
ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H32FeN4O4 / Feature type: SUBJECT OF INVESTIGATION
#12: Chemical
ChemComp-HEC / HEME C / Heme C


Mass: 618.503 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H34FeN4O4 / Feature type: SUBJECT OF INVESTIGATION
#13: Chemical
ChemComp-HEA / HEME-A / Heme A


Mass: 852.837 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C49H56FeN4O6 / Feature type: SUBJECT OF INVESTIGATION

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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: electron tomography

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Sample preparation

ComponentName: Cytochrome bcc:aa3 supercomplex / Type: COMPLEX / Entity ID: #1-#9 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Mycobacterium tuberculosis variant bovis BCG (bacteria)
Source (recombinant)Organism: Mycobacterium tuberculosis variant bovis BCG (bacteria)
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 FIELDBright-field microscopy / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 40 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionNum. of particles: 100
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00340095
ELECTRON MICROSCOPYf_angle_d0.62454837
ELECTRON MICROSCOPYf_dihedral_angle_d6.3935451
ELECTRON MICROSCOPYf_chiral_restr0.0425976
ELECTRON MICROSCOPYf_plane_restr0.0046855

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