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Yorodumi- PDB-8xsx: Cryo-EM structure of the human 80S ribosome with Tigecycline, E-t... -
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Open data
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Basic information
| Entry | Database: PDB / ID: 8xsx | ||||||
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| Title | Cryo-EM structure of the human 80S ribosome with Tigecycline, E-tRNA, SERBP1 and eEF2 | ||||||
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Keywords | RIBOSOME / Tigecycline / antibiotic / eEF2 / SERBP1 | ||||||
| Function / homology | Function and homology informationSynthesis of diphthamide-EEF2 / translation at postsynapse / ribosome hibernation / translation elongation factor binding / PML body organization / SUMO binding / response to folic acid / translation at presynapse / exit from mitosis / eukaryotic 80S initiation complex ...Synthesis of diphthamide-EEF2 / translation at postsynapse / ribosome hibernation / translation elongation factor binding / PML body organization / SUMO binding / response to folic acid / translation at presynapse / exit from mitosis / eukaryotic 80S initiation complex / negative regulation of protein neddylation / response to insecticide / optic nerve development / negative regulation of endoplasmic reticulum unfolded protein response / regulation of translation involved in cellular response to UV / oxidized pyrimidine DNA binding / response to TNF agonist / positive regulation of base-excision repair / axial mesoderm development / positive regulation of respiratory burst involved in inflammatory response / negative regulation of formation of translation preinitiation complex / regulation of G1 to G0 transition / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage / ribosomal protein import into nucleus / positive regulation of gastrulation / positive regulation of cytoplasmic translation / protein tyrosine kinase inhibitor activity / positive regulation of endodeoxyribonuclease activity / IRE1-RACK1-PP2A complex / nucleolus organization / protein-DNA complex disassembly / positive regulation of Golgi to plasma membrane protein transport / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / 90S preribosome assembly / retinal ganglion cell axon guidance / TNFR1-mediated ceramide production / negative regulation of DNA repair / negative regulation of RNA splicing / GAIT complex / positive regulation of DNA damage response, signal transduction by p53 class mediator / supercoiled DNA binding / neural crest cell differentiation / TORC2 complex binding / alpha-beta T cell differentiation / NF-kappaB complex / G1 to G0 transition / cysteine-type endopeptidase activator activity involved in apoptotic process / oxidized purine DNA binding / aggresome / positive regulation of ubiquitin-protein transferase activity / negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide / regulation of establishment of cell polarity / negative regulation of bicellular tight junction assembly / ubiquitin-like protein conjugating enzyme binding / middle ear morphogenesis / negative regulation of phagocytosis / rRNA modification in the nucleus and cytosol / erythrocyte homeostasis / Formation of the ternary complex, and subsequently, the 43S complex / cytoplasmic side of rough endoplasmic reticulum membrane / laminin receptor activity / negative regulation of ubiquitin protein ligase activity / protein kinase A binding / ion channel inhibitor activity / Ribosomal scanning and start codon recognition / homeostatic process / pigmentation / Translation initiation complex formation / lncRNA binding / positive regulation of mitochondrial depolarization / Uptake and function of diphtheria toxin / positive regulation of T cell receptor signaling pathway / macrophage chemotaxis / negative regulation of Wnt signaling pathway / fibroblast growth factor binding / lung morphogenesis / monocyte chemotaxis / male meiosis I / positive regulation of natural killer cell proliferation / positive regulation of activated T cell proliferation / negative regulation of translational frameshifting / TOR signaling / Protein hydroxylation / BH3 domain binding / SARS-CoV-1 modulates host translation machinery / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / iron-sulfur cluster binding / regulation of cell division / cellular response to ethanol / mTORC1-mediated signalling / Peptide chain elongation / Selenocysteine synthesis / Formation of a pool of free 40S subunits / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / skeletal muscle cell differentiation / endonucleolytic cleavage to generate mature 3'-end of SSU-rRNA from (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / Eukaryotic Translation Termination / ubiquitin ligase inhibitor activity / positive regulation of GTPase activity / cellular response to actinomycin D Similarity search - Function | ||||||
| Biological species | Homo sapiens (human) | ||||||
| Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.4 Å | ||||||
Authors | Li, X. / Wang, M. / Cheng, J. | ||||||
| Funding support | 1items
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Citation | Journal: Nat Commun / Year: 2024Title: Structural basis for differential inhibition of eukaryotic ribosomes by tigecycline. Authors: Xiang Li / Mengjiao Wang / Timo Denk / Robert Buschauer / Yi Li / Roland Beckmann / Jingdong Cheng / ![]() Abstract: Tigecycline is widely used for treating complicated bacterial infections for which there are no effective drugs. It inhibits bacterial protein translation by blocking the ribosomal A-site. However, ...Tigecycline is widely used for treating complicated bacterial infections for which there are no effective drugs. It inhibits bacterial protein translation by blocking the ribosomal A-site. However, even though it is also cytotoxic for human cells, the molecular mechanism of its inhibition remains unclear. Here, we present cryo-EM structures of tigecycline-bound human mitochondrial 55S, 39S, cytoplasmic 80S and yeast cytoplasmic 80S ribosomes. We find that at clinically relevant concentrations, tigecycline effectively targets human 55S mitoribosomes, potentially, by hindering A-site tRNA accommodation and by blocking the peptidyl transfer center. In contrast, tigecycline does not bind to human 80S ribosomes under physiological concentrations. However, at high tigecycline concentrations, in addition to blocking the A-site, both human and yeast 80S ribosomes bind tigecycline at another conserved binding site restricting the movement of the L1 stalk. In conclusion, the observed distinct binding properties of tigecycline may guide new pathways for drug design and therapy. | ||||||
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Structure visualization
| Structure viewer | Molecule: Molmil Jmol/JSmol |
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Downloads & links
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Download
| PDBx/mmCIF format | 8xsx.cif.gz | 5 MB | Display | PDBx/mmCIF format |
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| PDB format | pdb8xsx.ent.gz | Display | PDB format | |
| PDBx/mmJSON format | 8xsx.json.gz | Tree view | PDBx/mmJSON format | |
| Others | Other downloads |
-Validation report
| Summary document | 8xsx_validation.pdf.gz | 2.5 MB | Display | wwPDB validaton report |
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| Full document | 8xsx_full_validation.pdf.gz | 2.5 MB | Display | |
| Data in XML | 8xsx_validation.xml.gz | 379.7 KB | Display | |
| Data in CIF | 8xsx_validation.cif.gz | 668.3 KB | Display | |
| Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/xs/8xsx ftp://data.pdbj.org/pub/pdb/validation_reports/xs/8xsx | HTTPS FTP |
-Related structure data
| Related structure data | ![]() 38629MC ![]() 8k2aC ![]() 8k2bC ![]() 8k2cC ![]() 8k2dC ![]() 8k82C ![]() 8xsyC ![]() 8xszC ![]() 8xt0C ![]() 8xt1C ![]() 8xt2C ![]() 8xt3C ![]() 8yooC ![]() 8yopC M: map data used to model this data C: citing same article ( |
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| Similar structure data | Similarity search - Function & homology F&H Search |
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Links
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Assembly
| Deposited unit | ![]()
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Components
-RNA chain , 5 types, 5 molecules L5L7L8S2CC
| #1: RNA chain | Mass: 1640182.000 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: GenBank: 86475748 |
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| #2: RNA chain | Mass: 38998.078 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: GenBank: 23898 |
| #3: RNA chain | Mass: 50449.812 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: GenBank: 555853 |
| #49: RNA chain | Mass: 602776.875 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: GenBank: 36162 |
| #85: RNA chain | Mass: 24231.510 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: GenBank: 174924 |
+60S ribosomal protein ... , 43 types, 43 molecules LALBLCLDLELFLGLHLILJLKLLLMLNLOLPLQLRLSLTLULVLWLXLYLZLaLbLcLd...
-Protein , 7 types, 7 molecules LmLsSgSfCACBCD
| #42: Protein | Mass: 14758.394 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P62987 |
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| #47: Protein | Mass: 34309.418 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P05388 |
| #70: Protein | Mass: 35115.652 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P63244 |
| #82: Protein | Mass: 18004.041 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P62979 |
| #83: Protein | Mass: 43851.879 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: Q9UQ80 |
| #84: Protein | Mass: 95463.211 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)References: UniProt: P13639, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement |
| #86: Protein | Mass: 44341.781 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: Q8NC51 |
+40S ribosomal protein ... , 31 types, 31 molecules SASBSDSESFSHSISKSLSPSQSRSSSTSUSVSXSaScSdSCSGSJSMSNSOSWSYSZSbSe
-Non-polymers , 4 types, 275 molecules 






| #87: Chemical | ChemComp-MG / #88: Chemical | ChemComp-T1C / #89: Chemical | ChemComp-ZN / #90: Chemical | ChemComp-ADP / | |
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-Details
| Has ligand of interest | Y |
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-Experimental details
-Experiment
| Experiment | Method: ELECTRON MICROSCOPY |
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| EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
| Component | Name: 80S ribosome with tigecycline, E-tRNA, eEF2 and SERBP1 Type: RIBOSOME / Entity ID: #1-#86 / Source: NATURAL |
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| Source (natural) | Organism: Homo sapiens (human) |
| Buffer solution | pH: 7.4 |
| Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
| Specimen support | Grid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3 |
| Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
| Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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| Microscopy | Model: FEI TITAN KRIOS |
| Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
| Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm |
| Specimen holder | Cryogen: NITROGEN |
| Image recording | Electron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) |
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Processing
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| CTF correction | Details: Relion / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | |||||||||||||||||||||
| Symmetry | Point symmetry: C1 (asymmetric) | |||||||||||||||||||||
| 3D reconstruction | Resolution: 2.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 88213 / Symmetry type: POINT | |||||||||||||||||||||
| Atomic model building | Protocol: RIGID BODY FIT / Space: REAL | |||||||||||||||||||||
| Atomic model building | PDB-ID: 6Z6M Accession code: 6Z6M / Source name: PDB / Type: experimental model |
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Homo sapiens (human)
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FIELD EMISSION GUN
