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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 / PML body organization / ribosome hibernation / translation elongation factor binding / response to folic acid / SUMO binding / translation at presynapse / positive regulation of cytoplasmic translation / response to insecticide ...Synthesis of diphthamide-EEF2 / translation at postsynapse / PML body organization / ribosome hibernation / translation elongation factor binding / response to folic acid / SUMO binding / translation at presynapse / positive regulation of cytoplasmic translation / response to insecticide / regulation of translation involved in cellular response to UV / eukaryotic 80S initiation complex / ribosomal protein import into nucleus / negative regulation of endoplasmic reticulum unfolded protein response / regulation of G1 to G0 transition / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / 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 / positive regulation of respiratory burst involved in inflammatory response / positive regulation of gastrulation / protein tyrosine kinase inhibitor activity / IRE1-RACK1-PP2A complex / positive regulation of Golgi to plasma membrane protein transport / nucleolus organization / TNFR1-mediated ceramide production / negative regulation of formation of translation preinitiation complex / positive regulation of DNA damage response, signal transduction by p53 class mediator / positive regulation of ubiquitin-protein transferase activity / GAIT complex / positive regulation of DNA-templated transcription initiation / negative regulation of RNA splicing / negative regulation of DNA repair / TORC2 complex binding / G1 to G0 transition / PD-L1(CD274) glycosylation and translocation to plasma membrane / Enterobacterial factors antagonize host defense / erythrocyte homeostasis / supercoiled DNA binding / regulation of establishment of cell polarity / cysteine-type endopeptidase activator activity involved in apoptotic process / oxidized purine DNA binding / NF-kappaB complex / cytoplasmic translational initiation / rRNA modification in the nucleus and cytosol / negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide / negative regulation of phagocytosis / negative regulation of bicellular tight junction assembly / ubiquitin-like protein conjugating enzyme binding / Uptake and function of diphtheria toxin / cytoplasmic side of rough endoplasmic reticulum membrane / Formation of the ternary complex, and subsequently, the 43S complex / lncRNA binding / laminin receptor activity / skeletal muscle cell differentiation / negative regulation of myoblast fusion / ion channel inhibitor activity / protein kinase A binding / positive regulation of mitochondrial depolarization / male meiosis I / Ribosomal scanning and start codon recognition / PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA / Translation initiation complex formation / negative regulation of Wnt signaling pathway / Dengue Virus Genome Translation and Replication / Maturation of DENV proteins / fibroblast growth factor binding / ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA / Protein hydroxylation / TOR signaling / BH3 domain binding / negative regulation of translational frameshifting / iron-sulfur cluster binding / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / monocyte chemotaxis / mTORC1-mediated signalling / SARS-CoV-1 modulates host translation machinery / regulation of cell division / positive regulation of GTPase activity / translational elongation / Peptide chain elongation / cellular response to ethanol / protein targeting / Selenocysteine synthesis / Dengue Virus Attachment and Entry / Formation of a pool of free 40S subunits / negative regulation of protein binding / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / Eukaryotic Translation Termination / negative regulation of respiratory burst involved in inflammatory response / protein serine/threonine kinase inhibitor activity / protein localization to nucleus / SRP-dependent cotranslational protein targeting to membrane / Response of EIF2AK4 (GCN2) to amino acid deficiency / AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274) / negative regulation of ubiquitin-dependent protein catabolic process / glial cell proliferation / ubiquitin ligase inhibitor activity 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
