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- PDB-7e1w: Cryo-EM structure of hybrid respiratory supercomplex consisting o... -

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Basic information

Entry
Database: PDB / ID: 7e1w
TitleCryo-EM structure of hybrid respiratory supercomplex consisting of Mycobacterium tuberculosis complexIII and Mycobacterium smegmatis complexIV in the presence of Q203
Components
  • (Cytochrome bc1 complex cytochrome ...) x 2
  • (Cytochrome c oxidase subunit ...) x 4
  • Cytochrome bc1 complex Rieske iron-sulfur subunit
  • Cytochrome c oxidase polypeptide 4
  • Prokaryotic respiratory supercomplex associate factor 1 PRSAF1
  • Uncharacterized protein MSMEG_4692/MSMEI_4575
KeywordsOXIDOREDUCTASE / Mycobacterium smegmatis / mycobacterium tuberculosis / complexIII / complexIV / electron transport / anti-TB drugs
Function / homology
Function and homology information


aerobic electron transport chain / cytochrome-c oxidase / quinol-cytochrome-c reductase / quinol-cytochrome-c reductase activity / cytochrome-c oxidase activity / oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen / ATP synthesis coupled electron transport / peptidoglycan-based cell wall / respiratory electron transport chain / monooxygenase activity ...aerobic electron transport chain / cytochrome-c oxidase / quinol-cytochrome-c reductase / quinol-cytochrome-c reductase activity / cytochrome-c oxidase activity / oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen / ATP synthesis coupled electron transport / peptidoglycan-based cell wall / respiratory electron transport chain / monooxygenase activity / electron transport chain / 2 iron, 2 sulfur cluster binding / oxidoreductase activity / iron ion binding / copper ion binding / heme binding / metal ion binding / membrane / plasma membrane
Similarity search - Function
Protein of unknown function DUF5130 / Domain of unknown function (DUF5130) / Cytochrome bc1 complex, cytochrome c subunit / Cytochrome c oxidase subunit IV, actinobacteria / QcrA subunit, N-terminal / Cytochrome c oxidase subunit IV / QcrA subunit N-terminal region / Cytochrome b(N-terminal)/b6/petB / : / Cytochrome c oxidase, subunit III, four-helix bundle ...Protein of unknown function DUF5130 / Domain of unknown function (DUF5130) / Cytochrome bc1 complex, cytochrome c subunit / Cytochrome c oxidase subunit IV, actinobacteria / QcrA subunit, N-terminal / Cytochrome c oxidase subunit IV / QcrA subunit N-terminal region / Cytochrome b(N-terminal)/b6/petB / : / Cytochrome c oxidase, subunit III, four-helix bundle / Cytochrome Bc1 Complex; Chain C / Cytochrome Bc1 Complex; Chain C / Cytochrome C Oxidase; Chain A / Cytochrome c oxidase-like, subunit I domain / 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/quinol oxidase subunit II / Cytochrome C oxidase subunit II, transmembrane domain superfamily / Copper centre Cu(A) / CO II and nitrous oxide reductase dinuclear copper centers signature. / Cytochrome C oxidase subunit II, periplasmic domain / Cytochrome c oxidase subunit II-like C-terminal / Cytochrome oxidase subunit II copper A binding domain profile. / Cytochrome b/b6, N-terminal / Cytochrome b/b6-like domain superfamily / Cytochrome b/b6 N-terminal region profile. / Di-haem cytochrome, transmembrane / Cytochrome c / Rieske iron-sulphur protein / 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 / Cupredoxin / Four Helix Bundle (Hemerythrin (Met), subunit A) / Prokaryotic membrane lipoprotein lipid attachment site profile. / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-9Y0 / Chem-9YF / CARDIOLIPIN / COPPER (II) ION / FE2/S2 (INORGANIC) CLUSTER / HEME-A / HEME C / PROTOPORPHYRIN IX CONTAINING FE / Chem-HUU / MENAQUINONE-9 ...Chem-9Y0 / Chem-9YF / CARDIOLIPIN / COPPER (II) ION / FE2/S2 (INORGANIC) CLUSTER / HEME-A / HEME C / PROTOPORPHYRIN IX CONTAINING FE / Chem-HUU / MENAQUINONE-9 / PALMITIC ACID / Probable cytochrome c oxidase subunit 3 / Cytochrome c oxidase polypeptide 4 / cytochrome-c oxidase / Uncharacterized protein MSMEG_4692/MSMEI_4575 / Uncharacterized protein / Cytochrome bc1 complex Rieske iron-sulfur subunit / Cytochrome bc1 complex cytochrome c subunit / Cytochrome bc1 complex cytochrome b subunit
Similarity search - Component
Biological speciesMycobacterium tuberculosis H37Rv (bacteria)
Mycobacterium smegmatis MC2 51 (bacteria)
Mycolicibacterium smegmatis MC2 51 (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.67 Å
AuthorsZhou, S. / Wang, W. / Gao, Y. / Gong, H. / Rao, Z.
Funding support China, 5items
OrganizationGrant numberCountry
Chinese Academy of SciencesXDB37030201 China
Chinese Academy of SciencesXDB37020203 China
Chinese Academy of Sciences2017YFC0840300 China
National Natural Science Foundation of China (NSFC)81520108019 China
National Natural Science Foundation of China (NSFC)813300237 China
CitationJournal: Elife / Year: 2021
Title: Structure of cytochrome in complex with Q203 and TB47, two anti-TB drug candidates.
Authors: Shan Zhou / Weiwei Wang / Xiaoting Zhou / Yuying Zhang / Yuezheng Lai / Yanting Tang / Jinxu Xu / Dongmei Li / Jianping Lin / Xiaolin Yang / Ting Ran / Hongming Chen / Luke W Guddat / Quan ...Authors: Shan Zhou / Weiwei Wang / Xiaoting Zhou / Yuying Zhang / Yuezheng Lai / Yanting Tang / Jinxu Xu / Dongmei Li / Jianping Lin / Xiaolin Yang / Ting Ran / Hongming Chen / Luke W Guddat / Quan Wang / Yan Gao / Zihe Rao / Hongri Gong /
Abstract: Pathogenic mycobacteria pose a sustained threat to global human health. Recently, cytochrome complexes have gained interest as targets for antibiotic drug development. However, there is currently no ...Pathogenic mycobacteria pose a sustained threat to global human health. Recently, cytochrome complexes have gained interest as targets for antibiotic drug development. However, there is currently no structural information for the cytochrome complex from these pathogenic mycobacteria. Here, we report the structures of cytochrome alone (2.68 Å resolution) and in complex with clinical drug candidates Q203 (2.67 Å resolution) and TB47 (2.93 Å resolution) determined by single-particle cryo-electron microscopy. cytochrome forms a dimeric assembly with endogenous menaquinone/menaquinol bound at the quinone/quinol-binding pockets. We observe Q203 and TB47 bound at the quinol-binding site and stabilized by hydrogen bonds with the side chains of Thr and Glu, residues that are conserved across pathogenic mycobacteria. These high-resolution images provide a basis for the design of new mycobacterial cytochrome inhibitors that could be developed into broad-spectrum drugs to treat mycobacterial infections.
History
DepositionFeb 3, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 27, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 20, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Jul 27, 2022Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Oct 16, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature / pdbx_validate_chiral
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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  • Deposited structure unit
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Assembly

Deposited unit
E: Cytochrome c oxidase subunit 2
F: Cytochrome c oxidase subunit 1
G: Cytochrome c oxidase subunit 3
H: Cytochrome c oxidase polypeptide 4
I: Cytochrome c oxidase subunit CtaJ
J: Uncharacterized protein MSMEG_4692/MSMEI_4575
D: Prokaryotic respiratory supercomplex associate factor 1 PRSAF1
Q: Cytochrome c oxidase subunit 2
R: Cytochrome c oxidase subunit 1
S: Cytochrome c oxidase subunit 3
T: Cytochrome c oxidase polypeptide 4
U: Cytochrome c oxidase subunit CtaJ
V: Uncharacterized protein MSMEG_4692/MSMEI_4575
P: Prokaryotic respiratory supercomplex associate factor 1 PRSAF1
N: Cytochrome bc1 complex cytochrome b subunit
M: Cytochrome bc1 complex Rieske iron-sulfur subunit
O: Cytochrome bc1 complex cytochrome c subunit
B: Cytochrome bc1 complex cytochrome b subunit
A: Cytochrome bc1 complex Rieske iron-sulfur subunit
C: Cytochrome bc1 complex cytochrome c subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)672,22479
Polymers624,85420
Non-polymers47,37059
Water181
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area193040 Å2
ΔGint-1810 kcal/mol
Surface area176840 Å2

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Components

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Cytochrome c oxidase subunit ... , 4 types, 8 molecules EQFRGSIU

#1: Protein Cytochrome c oxidase subunit 2 / Cytochrome C oxidase subunit II ctaC


Mass: 38077.465 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mycobacterium smegmatis MC2 51 (bacteria) / References: UniProt: A0R057, cytochrome-c oxidase
#2: Protein Cytochrome c oxidase subunit 1


Mass: 64162.965 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) Mycolicibacterium smegmatis MC2 51 (bacteria)
#3: Protein Cytochrome c oxidase subunit 3 / Cytochrome c oxidase subunit 3 CtaE


Mass: 22196.883 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mycobacterium smegmatis MC2 51 (bacteria) / References: UniProt: A0R049
#5: Protein Cytochrome c oxidase subunit CtaJ


Mass: 8365.549 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mycobacterium smegmatis MC2 51 (bacteria) / References: UniProt: A0R1B6

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Protein , 4 types, 8 molecules HTJVDPMA

#4: Protein Cytochrome c oxidase polypeptide 4 / Cytochrome aa3 subunit 4 / Cytochrome c oxidase polypeptide IV


Mass: 15177.424 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mycobacterium smegmatis MC2 51 (bacteria) / References: UniProt: A0R056, cytochrome-c oxidase
#6: Protein Uncharacterized protein MSMEG_4692/MSMEI_4575 / Cytochrome c oxidase subunit CtaI


Mass: 15910.971 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mycobacterium smegmatis MC2 51 (bacteria) / References: UniProt: A0R1B5
#7: Protein Prokaryotic respiratory supercomplex associate factor 1 PRSAF1


Mass: 11329.909 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Source: (natural) Mycolicibacterium smegmatis MC2 51 (bacteria)
#9: Protein Cytochrome bc1 complex Rieske iron-sulfur subunit / Cytochrome bc1 reductase complex subunit QcrA / Rieske iron-sulfur protein / Ubiquinol--cytochrome ...Cytochrome bc1 reductase complex subunit QcrA / Rieske iron-sulfur protein / Ubiquinol--cytochrome c reductase iron-sulfur subunit


Mass: 46976.465 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis H37Rv (bacteria)
Strain: H37Rv / Gene: qcrA, Rv2195, MTCY190.06
Production host: Mycolicibacterium smegmatis MC2 51 (bacteria)
References: UniProt: P9WH23

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

#8: Protein Cytochrome bc1 complex cytochrome b subunit / Cytochrome bc1 reductase complex subunit QcrB / Ubiquinol--cytochrome c reductase cytochrome b subunit


Mass: 61077.062 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis H37Rv (bacteria)
Strain: H37Rv / Gene: qcrB, Rv2196, MTCY190.07
Production host: Mycolicibacterium smegmatis MC2 51 (bacteria)
References: UniProt: P9WP37, quinol-cytochrome-c reductase
#10: Protein Cytochrome bc1 complex cytochrome c subunit / Cytochrome bc1 reductase complex subunit QcrC / Ubiquinol--cytochrome c reductase cytochrome c subunit


Mass: 29152.365 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis H37Rv (bacteria)
Strain: H37Rv / Gene: qcrC, Rv2194, MTCY190.05
Production host: Mycolicibacterium smegmatis MC2 51 (bacteria)
References: UniProt: P9WP35, quinol-cytochrome-c reductase

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Non-polymers , 12 types, 60 molecules

#11: Chemical
ChemComp-CU / COPPER (II) ION


Mass: 63.546 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Cu
#12: 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.: 17 / Source method: obtained synthetically / Formula: C81H156O17P2 / Comment: phospholipid*YM
#13: Chemical
ChemComp-PLM / PALMITIC ACID


Mass: 256.424 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C16H32O2 / Feature type: SUBJECT OF INVESTIGATION
#14: Chemical
ChemComp-HEA / HEME-A


Mass: 852.837 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C49H56FeN4O6 / Feature type: SUBJECT OF INVESTIGATION
#15: Chemical ChemComp-9Y0 / (2R)-3-(((2-aminoethoxy)(hydroxy)phosphoryl)oxy)-2-(palmitoyloxy)propyl (E)-octadec-9-enoate


Mass: 717.996 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C39H76NO8P / Feature type: SUBJECT OF INVESTIGATION
#16: 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
#17: Chemical
ChemComp-MQ9 / MENAQUINONE-9


Mass: 785.233 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C56H80O2 / Feature type: SUBJECT OF INVESTIGATION
#18: Chemical ChemComp-HUU / 6-chloranyl-2-ethyl-N-[[4-[4-[4-(trifluoromethyloxy)phenyl]piperidin-1-yl]phenyl]methyl]imidazo[1,2-a]pyridine-3-carboxamide / Telacebec


Mass: 557.006 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H28ClF3N4O2 / Feature type: SUBJECT OF INVESTIGATION
#19: Chemical ChemComp-FES / FE2/S2 (INORGANIC) CLUSTER


Mass: 175.820 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Fe2S2
#20: Chemical
ChemComp-9YF / (2R)-2-(hexadecanoyloxy)-3-{[(S)-hydroxy{[(1R,2R,3R,4R,5R,6S)-2,3,4,5,6-pentahydroxycyclohexyl]oxy}phosphoryl]oxy}propyl (9S)-9-methyloctadecanoate


Mass: 853.112 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C44H85O13P / Feature type: SUBJECT OF INVESTIGATION
#21: Chemical
ChemComp-HEC / HEME C


Mass: 618.503 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H34FeN4O4 / Feature type: SUBJECT OF INVESTIGATION
#22: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / 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: hybrid respiratory supercomplex consisting of Mycobacterium tuberculosis complexIII and Mycobacterium smegmatis complexIV in the presence of Q203
Type: COMPLEX / Entity ID: #1-#10 / Source: NATURAL
Molecular weightValue: 0.8 MDa / Experimental value: YES
Source (natural)Organism: Mycolicibacterium smegmatis MC2 51 (bacteria)
Buffer solutionpH: 7.4
SpecimenConc.: 10 mg/ml / Embedding 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 / Calibrated defocus min: 1200 nm / Calibrated defocus max: 1800 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.67 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 106770 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00344215
ELECTRON MICROSCOPYf_angle_d0.62959987
ELECTRON MICROSCOPYf_dihedral_angle_d13.04725097
ELECTRON MICROSCOPYf_chiral_restr0.0446289
ELECTRON MICROSCOPYf_plane_restr0.0057270

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