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Yorodumi- PDB-6ole: Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug... -
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-Basic information
Entry | Database: PDB / ID: 6ole | ||||||
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Title | Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug-like molecule with AP and PE tRNAs | ||||||
Components |
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Keywords | RIBOSOME / selective stalling / drug-like molecule / human ribosome nascent chain complex | ||||||
Function / homology | Function and homology information response to Gram-positive bacterium / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / pituitary gland development / gamma-catenin binding / negative regulation of axon extension / cell-cell adhesion mediated by cadherin / cellular response to indole-3-methanol / flotillin complex / calcium-dependent cell-cell adhesion via plasma membrane cell adhesion molecules / Formation of definitive endoderm ...response to Gram-positive bacterium / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / pituitary gland development / gamma-catenin binding / negative regulation of axon extension / cell-cell adhesion mediated by cadherin / cellular response to indole-3-methanol / flotillin complex / calcium-dependent cell-cell adhesion via plasma membrane cell adhesion molecules / Formation of definitive endoderm / eukaryotic 80S initiation complex / negative regulation of protein neddylation / embryonic brain development / positive regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis / negative regulation of endoplasmic reticulum unfolded protein response / translation at presynapse / oxidized pyrimidine DNA binding / response to TNF agonist / positive regulation of base-excision repair / protein tyrosine kinase inhibitor activity / axial mesoderm development / positive regulation of respiratory burst involved in inflammatory response / ribosomal protein import into nucleus / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / negative regulation of formation of translation preinitiation complex / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage / positive regulation of gastrulation / nucleolus organization / IRE1-RACK1-PP2A complex / 90S preribosome assembly / positive regulation of endodeoxyribonuclease activity / positive regulation of Golgi to plasma membrane protein transport / TNFR1-mediated ceramide production / catenin complex / Apoptotic cleavage of cell adhesion proteins / negative regulation of DNA repair / negative regulation of RNA splicing / TORC2 complex binding / Adherens junctions interactions / GAIT complex / GTPase activating protein binding / negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide / oxidized purine DNA binding / supercoiled DNA binding / neural crest cell differentiation / middle ear morphogenesis / cell-cell junction assembly / NF-kappaB complex / adherens junction organization / ubiquitin-like protein conjugating enzyme binding / regulation of establishment of cell polarity / negative regulation of phagocytosis / positive regulation of ubiquitin-protein transferase activity / rRNA modification in the nucleus and cytosol / A band / Formation of the ternary complex, and subsequently, the 43S complex / erythrocyte homeostasis / cytoplasmic side of rough endoplasmic reticulum membrane / alpha-beta T cell differentiation / regulation of G1 to G0 transition / laminin receptor activity / apical junction complex / exit from mitosis / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / regulation of translation involved in cellular response to UV / ankyrin binding / protein-DNA complex disassembly / protein kinase A binding / positive regulation of DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / optic nerve development / negative regulation of ubiquitin protein ligase activity / Ribosomal scanning and start codon recognition / ion channel inhibitor activity / response to aldosterone / Translation initiation complex formation / pigmentation / retinal ganglion cell axon guidance / positive regulation of mitochondrial depolarization / mammalian oogenesis stage / G1 to G0 transition / negative regulation of cell-cell adhesion / homeostatic process / cellular response to lithium ion / activation-induced cell death of T cells / macrophage chemotaxis / negative regulation of Wnt signaling pathway / lung morphogenesis / positive regulation of T cell receptor signaling pathway / fibroblast growth factor binding / positive regulation of activated T cell proliferation / iron-sulfur cluster binding / homophilic cell adhesion via plasma membrane adhesion molecules / regulation of cell division / Protein hydroxylation / monocyte chemotaxis / negative regulation of peptidyl-serine phosphorylation / BH3 domain binding / mTORC1-mediated signalling / SARS-CoV-1 modulates host translation machinery / Peptide chain elongation Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å | ||||||
Authors | Li, W. / Cate, J.H.D. | ||||||
Funding support | United States, 1items
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Citation | Journal: Nat Struct Mol Biol / Year: 2019 Title: Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule. Authors: Wenfei Li / Fred R Ward / Kim F McClure / Stacey Tsai-Lan Chang / Elizabeth Montabana / Spiros Liras / Robert G Dullea / Jamie H D Cate / Abstract: The drug-like molecule PF-06446846 (PF846) binds the human ribosome and selectively blocks the translation of a small number of proteins by an unknown mechanism. In structures of PF846-stalled human ...The drug-like molecule PF-06446846 (PF846) binds the human ribosome and selectively blocks the translation of a small number of proteins by an unknown mechanism. In structures of PF846-stalled human ribosome nascent chain complexes, PF846 binds in the ribosome exit tunnel in a eukaryotic-specific pocket formed by 28S ribosomal RNA, and alters the path of the nascent polypeptide chain. PF846 arrests the translating ribosome in the rotated state of translocation, in which the peptidyl-transfer RNA 3'-CCA end is improperly docked in the peptidyl transferase center. Selections of messenger RNAs from mRNA libraries using translation extracts reveal that PF846 can stall translation elongation, arrest termination or even enhance translation, depending on nascent chain sequence context. These results illuminate how a small molecule selectively targets translation by the human ribosome, and provides a foundation for developing small molecules that modulate the production of proteins of therapeutic interest. | ||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 6ole.cif.gz | 4.6 MB | Display | PDBx/mmCIF format |
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PDB format | pdb6ole.ent.gz | Display | PDB format | |
PDBx/mmJSON format | 6ole.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 6ole_validation.pdf.gz | 2 MB | Display | wwPDB validaton report |
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Full document | 6ole_full_validation.pdf.gz | 2.2 MB | Display | |
Data in XML | 6ole_validation.xml.gz | 364.9 KB | Display | |
Data in CIF | 6ole_validation.cif.gz | 615.1 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/ol/6ole ftp://data.pdbj.org/pub/pdb/validation_reports/ol/6ole | HTTPS FTP |
-Related structure data
Related structure data | 0600MC 0526C 0596C 0597C 0598C 0599C 0601C 6olfC 6olgC 6oliC 6olzC 6om0C 6om7C M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-RNA chain , 7 types, 7 molecules S2DEtuvw
#1: RNA chain | Mass: 553505.062 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) |
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#38: RNA chain | Mass: 50449.812 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) |
#39: RNA chain | Mass: 38998.078 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) |
#79: RNA chain | Mass: 1168718.500 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) |
#80: RNA chain | Mass: 24414.451 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) |
#81: RNA chain | Mass: 24436.508 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) |
#82: RNA chain | Mass: 3193.932 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) |
+40S ribosomal protein ... , 32 types, 32 molecules SASBSDSESFSHSISKSLSPSQSRSSSTSUSVSXSaScSdSCSGSJSMSNSOSWSYSZSbSeSf
+60S ribosomal protein ... , 42 types, 42 molecules ABCFGHIJKLMNOPQRSTUVWXYZabcdef...
-Protein / Protein/peptide , 2 types, 2 molecules Sgy
#22: Protein | Mass: 34568.012 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P63244 |
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#83: Protein/peptide | Mass: 4010.057 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P12830 |
-Non-polymers , 4 types, 52 molecules
#84: Chemical | ChemComp-MG / #85: Chemical | ChemComp-ZN / #86: Chemical | ChemComp-MVM / | #87: Water | ChemComp-HOH / | |
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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 |
-Sample preparation
Component | Name: Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug-like molecule with AP and PE tRNAs Type: RIBOSOME / Entity ID: #1-#83 / Source: NATURAL |
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Source (natural) | Organism: Homo sapiens (human) |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Details: unspecified |
Vitrification | Cryogen name: ETHANE |
-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 |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
CTF correction | Type: NONE |
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3D reconstruction | Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 73110 / Symmetry type: POINT |