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Yorodumi- PDB-8xsx: Cryo-EM structure of the human 80S ribosome with Tigecycline, E-t... -
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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 / response to folic acid / SUMO binding / translation at presynapse / exit from mitosis / optic nerve development ...Synthesis of diphthamide-EEF2 / translation at postsynapse / ribosome hibernation / translation elongation factor binding / PML body organization / response to folic acid / SUMO binding / translation at presynapse / exit from mitosis / optic nerve development / positive regulation of cytoplasmic translation / response to insecticide / eukaryotic 80S initiation complex / regulation of translation involved in cellular response to UV / negative regulation of formation of translation preinitiation complex / axial mesoderm development / regulation of G1 to G0 transition / retinal ganglion cell axon guidance / negative regulation of endoplasmic reticulum unfolded protein response / ribosomal protein import into nucleus / oxidized pyrimidine DNA binding / response to TNF agonist / positive regulation of base-excision repair / protein-DNA complex disassembly / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / positive regulation of respiratory burst involved in inflammatory response / positive regulation of gastrulation / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage / protein tyrosine kinase inhibitor activity / 90S preribosome assembly / positive regulation of ubiquitin-protein transferase activity / IRE1-RACK1-PP2A complex / positive regulation of Golgi to plasma membrane protein transport / alpha-beta T cell differentiation / nucleolus organization / positive regulation of DNA-templated transcription initiation / aggresome / TNFR1-mediated ceramide production / GAIT complex / negative regulation of RNA splicing / positive regulation of DNA damage response, signal transduction by p53 class mediator / TORC2 complex binding / supercoiled DNA binding / negative regulation of DNA repair / neural crest cell differentiation / NF-kappaB complex / G1 to G0 transition / cytoplasmic translational initiation / oxidized purine DNA binding / cysteine-type endopeptidase activator activity involved in apoptotic process / middle ear morphogenesis / negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide / negative regulation of bicellular tight junction assembly / regulation of establishment of cell polarity / ubiquitin-like protein conjugating enzyme binding / rRNA modification in the nucleus and cytosol / negative regulation of phagocytosis / erythrocyte homeostasis / Formation of the ternary complex, and subsequently, the 43S complex / cytoplasmic side of rough endoplasmic reticulum membrane / Uptake and function of diphtheria toxin / protein kinase A binding / lncRNA binding / ion channel inhibitor activity / laminin receptor activity / Ribosomal scanning and start codon recognition / homeostatic process / pigmentation / Translation initiation complex formation / positive regulation of mitochondrial depolarization / macrophage chemotaxis / lung morphogenesis / negative regulation of Wnt signaling pathway / positive regulation of natural killer cell proliferation / fibroblast growth factor binding / male meiosis I / negative regulation of translational frameshifting / TOR signaling / monocyte chemotaxis / BH3 domain binding / Protein hydroxylation / SARS-CoV-1 modulates host translation machinery / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / iron-sulfur cluster binding / mTORC1-mediated signalling / positive regulation of GTPase activity / Peptide chain elongation / regulation of cell division / skeletal muscle cell differentiation / cellular response to ethanol / Selenocysteine synthesis / Formation of a pool of free 40S subunits / translational elongation / blastocyst development / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / Eukaryotic Translation Termination / protein serine/threonine kinase inhibitor activity / SRP-dependent cotranslational protein targeting to membrane / Response of EIF2AK4 (GCN2) to amino acid deficiency / Viral mRNA Translation 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
| Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/xs/8xsx ftp://data.pdbj.org/pub/pdb/validation_reports/xs/8xsx | HTTPS FTP |
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-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
