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Yorodumi- PDB-6om0: Human ribosome nascent chain complex (PCSK9-RNC) stalled by a dru... -
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-Basic information
Entry | Database: PDB / ID: 6om0 | ||||||
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Title | Human ribosome nascent chain complex (PCSK9-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 adenylosuccinate lyase / N6-(1,2-dicarboxyethyl)AMP AMP-lyase (fumarate-forming) activity / (S)-2-(5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido) succinate lyase (fumarate-forming) activity / eukaryotic 80S initiation complex / : / negative regulation of protein neddylation / 'de novo' AMP biosynthetic process / translation at presynapse / negative regulation of endoplasmic reticulum unfolded protein response / oxidized pyrimidine DNA binding ...adenylosuccinate lyase / N6-(1,2-dicarboxyethyl)AMP AMP-lyase (fumarate-forming) activity / (S)-2-(5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido) succinate lyase (fumarate-forming) activity / eukaryotic 80S initiation complex / : / negative regulation of protein neddylation / 'de novo' AMP biosynthetic process / translation at presynapse / negative regulation of endoplasmic reticulum unfolded protein response / oxidized pyrimidine DNA binding / response to TNF agonist / positive regulation of base-excision repair / axial mesoderm development / ribosomal protein import into nucleus / embryonic brain development / protein tyrosine kinase inhibitor activity / positive regulation of respiratory burst involved in inflammatory response / 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 / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / 90S preribosome assembly / IRE1-RACK1-PP2A complex / positive regulation of endodeoxyribonuclease activity / positive regulation of Golgi to plasma membrane protein transport / TNFR1-mediated ceramide production / negative regulation of DNA repair / negative regulation of RNA splicing / GAIT complex / negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide / supercoiled DNA binding / oxidized purine DNA binding / neural crest cell differentiation / NF-kappaB complex / middle ear morphogenesis / ubiquitin-like protein conjugating enzyme binding / negative regulation of phagocytosis / regulation of establishment of cell polarity / positive regulation of ubiquitin-protein transferase activity / A band / rRNA modification in the nucleus and cytosol / erythrocyte homeostasis / Formation of the ternary complex, and subsequently, the 43S complex / alpha-beta T cell differentiation / cytoplasmic side of rough endoplasmic reticulum membrane / regulation of G1 to G0 transition / exit from mitosis / laminin receptor activity / pigmentation / 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 / protein-DNA complex disassembly / positive regulation of DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / protein kinase A binding / negative regulation of ubiquitin protein ligase activity / 'de novo' IMP biosynthetic process / optic nerve development / Ribosomal scanning and start codon recognition / ion channel inhibitor activity / response to aldosterone / Translation initiation complex formation / retinal ganglion cell axon guidance / fibroblast growth factor binding / mammalian oogenesis stage / homeostatic process / positive regulation of mitochondrial depolarization / G1 to G0 transition / activation-induced cell death of T cells / positive regulation of T cell receptor signaling pathway / macrophage chemotaxis / negative regulation of Wnt signaling pathway / lung morphogenesis / negative regulation of peptidyl-serine phosphorylation / iron-sulfur cluster binding / positive regulation of activated T cell proliferation / monocyte chemotaxis / Protein hydroxylation / regulation of cell division / BH3 domain binding / cysteine-type endopeptidase activator activity involved in apoptotic process / mTORC1-mediated signalling / SARS-CoV-1 modulates host translation machinery / Peptide chain elongation / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / Selenocysteine synthesis / positive regulation of signal transduction by p53 class mediator / Formation of a pool of free 40S subunits / blastocyst development / ubiquitin ligase inhibitor activity / Eukaryotic Translation Termination / phagocytic cup / negative regulation of respiratory burst involved in inflammatory response / Response of EIF2AK4 (GCN2) to amino acid deficiency / SRP-dependent cotranslational protein targeting to membrane / Viral mRNA Translation / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / protein localization to nucleus / Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) / GTP hydrolysis and joining of the 60S ribosomal subunit 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 | 6om0.cif.gz | 4.6 MB | Display | PDBx/mmCIF format |
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PDB format | pdb6om0.ent.gz | Display | PDB format | |
PDBx/mmJSON format | 6om0.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 6om0_validation.pdf.gz | 2 MB | Display | wwPDB validaton report |
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Full document | 6om0_full_validation.pdf.gz | 2.2 MB | Display | |
Data in XML | 6om0_validation.xml.gz | 366.8 KB | Display | |
Data in CIF | 6om0_validation.cif.gz | 620.1 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/om/6om0 ftp://data.pdbj.org/pub/pdb/validation_reports/om/6om0 | HTTPS FTP |
-Related structure data
Related structure data | 0596MC 0526C 0597C 0598C 0599C 0600C 0601C 6oleC 6olfC 6olgC 6oliC 6olzC 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: 38385.750 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: 2886.409 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: Q8NBP7 |
-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 (PCSK9-RNC) stalled by a drug-like small 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: 43666 / Symmetry type: POINT |