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- EMDB-19493: Human mitochondrial ribosome in complex with antibiotic tigecycli... -

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Basic information

Entry
Database: EMDB / ID: EMD-19493
TitleHuman mitochondrial ribosome in complex with antibiotic tigecycline, Class P-tRNA consensus.
Map dataClass P-tRNA, consensus
Sample
  • Complex: Human mitochondrial ribosome in complex with mRNA, P-site tRNA and antibiotic tigecycline.
Keywordsantibiotics / immunometabolism / mitochondrial ribosomes / tetracyclines / T cells. / RIBOSOME
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsKhawaja A / Nguyen MD / Singh V / Rorbach J
Funding support Sweden, 1 items
OrganizationGrant numberCountry
Knut and Alice Wallenberg Foundation023405053 Sweden
CitationJournal: Nat Commun / Year: 2025
Title: T cell toxicity induced by tigecycline binding to the mitochondrial ribosome.
Authors: Qiuya Shao / Anas Khawaja / Minh Duc Nguyen / Vivek Singh / Jingdian Zhang / Yong Liu / Joel Nordin / Monika Adori / C Axel Innis / Xaquin Castro Dopico / Joanna Rorbach /
Abstract: Tetracyclines are essential bacterial protein synthesis inhibitors under continual development to combat antibiotic resistance yet suffer from unwanted side effects. Mitoribosomes - responsible for ...Tetracyclines are essential bacterial protein synthesis inhibitors under continual development to combat antibiotic resistance yet suffer from unwanted side effects. Mitoribosomes - responsible for generating oxidative phosphorylation (OXPHOS) subunits - share structural similarities with bacterial machinery and may suffer from cross-reactivity. Since lymphocytes rely upon OXPHOS upregulation to establish immunity, we set out to assess the impact of ribosome-targeting antibiotics on human T cells. We find tigecycline, a third-generation tetracycline, to be the most cytotoxic compound tested. In vitro, 5-10 μM tigecycline inhibits mitochondrial but not cytosolic translation, mitochondrial complex I, III and IV expression, and curtails the activation and expansion of unique T cell subsets. By cryo-EM, we find tigecycline to occupy three sites on T cell mitoribosomes. In addition to the conserved A-site found in bacteria, tigecycline also attaches to the peptidyl transferase center of the large subunit. Furthermore, a third, distinct binding site on the large subunit, aligns with helices analogous to those in bacteria, albeit lacking methylation in humans. The data provide a mechanism to explain part of the anti-inflammatory effects of these drugs and inform antibiotic design.
History
DepositionJan 26, 2024-
Header (metadata) releaseFeb 12, 2025-
Map releaseFeb 12, 2025-
UpdateMay 14, 2025-
Current statusMay 14, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_19493.png

Downloads & links

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Map

FileDownload / File: emd_19493.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationClass P-tRNA, consensus
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.01 Å/pix.
x 512 pix.
= 517.12 Å		1.01 Å/pix.
x 512 pix.
= 517.12 Å		1.01 Å/pix.
x 512 pix.
= 517.12 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.01 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-2.2552495 - 4.550495
Average (Standard dev.)0.005226567 (±0.06783628)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 517.12 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Class P-tRNA, consensus, half map B

Fileemd_19493_half_map_1.map
AnnotationClass P-tRNA, consensus, half map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Class P-tRNA, consensus, half map A

Fileemd_19493_half_map_2.map
AnnotationClass P-tRNA, consensus, half map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human mitochondrial ribosome in complex with mRNA, P-site tRNA an...

EntireName: Human mitochondrial ribosome in complex with mRNA, P-site tRNA and antibiotic tigecycline.
Components
  • Complex: Human mitochondrial ribosome in complex with mRNA, P-site tRNA and antibiotic tigecycline.

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Supramolecule #1: Human mitochondrial ribosome in complex with mRNA, P-site tRNA an...

SupramoleculeName: Human mitochondrial ribosome in complex with mRNA, P-site tRNA and antibiotic tigecycline.
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#86
Source (natural)Organism: Homo sapiens (human)

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 45.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.4 µm / Nominal magnification: 165000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7qi4

Final reconstructionNumber classes used: 1 / Resolution.type: BY AUTHOR / Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 87076
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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