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Yorodumi- EMDB-0597: Structure of a drug-like molecule stalled ribosome nascent chain ... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-0597 | |||||||||
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Title | Structure of a drug-like molecule stalled ribosome nascent chain complex (PCSK9-RNC) in rotated state with AA tRAN and PE tRNA | |||||||||
Map data | PF846 stalled human ribosome nascent chain complex (PCSK9-RNC) in rotated state with AA tRNA and PE tRNA; map is sharpened. | |||||||||
Sample |
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Function / homology | Function and homology information negative regulation of low-density lipoprotein particle receptor binding / negative regulation of receptor-mediated endocytosis involved in cholesterol transport / low-density lipoprotein particle receptor catabolic process / extrinsic component of external side of plasma membrane / PCSK9-LDLR complex / very-low-density lipoprotein particle binding / negative regulation of receptor recycling / PCSK9-AnxA2 complex / negative regulation of sodium ion transmembrane transporter activity / apolipoprotein receptor binding ...negative regulation of low-density lipoprotein particle receptor binding / negative regulation of receptor-mediated endocytosis involved in cholesterol transport / low-density lipoprotein particle receptor catabolic process / extrinsic component of external side of plasma membrane / PCSK9-LDLR complex / very-low-density lipoprotein particle binding / negative regulation of receptor recycling / PCSK9-AnxA2 complex / negative regulation of sodium ion transmembrane transporter activity / apolipoprotein receptor binding / negative regulation of low-density lipoprotein particle clearance / low-density lipoprotein particle binding / signaling receptor inhibitor activity / LDL clearance / positive regulation of low-density lipoprotein particle receptor catabolic process / lipoprotein metabolic process / positive regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis / negative regulation of endoplasmic reticulum unfolded protein response / embryonic brain development / oxidized pyrimidine DNA binding / eukaryotic 80S initiation complex / response to TNF agonist / very-low-density lipoprotein particle receptor binding / positive regulation of base-excision repair / negative regulation of protein neddylation / protein tyrosine kinase inhibitor activity / positive regulation of respiratory burst involved in inflammatory response / translation at presynapse / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage / positive regulation of gastrulation / axial mesoderm development / negative regulation of formation of translation preinitiation complex / nucleolus organization / ribosomal protein import into nucleus / negative regulation of low-density lipoprotein receptor activity / IRE1-RACK1-PP2A complex / : / positive regulation of endodeoxyribonuclease activity / positive regulation of Golgi to plasma membrane protein transport / 90S preribosome assembly / TNFR1-mediated ceramide production / negative regulation of receptor internalization / endolysosome membrane / negative regulation of RNA splicing / negative regulation of DNA repair / TORC2 complex binding / regulation of signaling receptor activity / sodium channel inhibitor activity / GAIT complex / negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide / oxidized purine DNA binding / supercoiled DNA binding / neural crest cell differentiation / NF-kappaB complex / middle ear morphogenesis / ubiquitin-like protein conjugating enzyme binding / regulation of establishment of cell polarity / negative regulation of phagocytosis / positive regulation of ubiquitin-protein transferase activity / Formation of the ternary complex, and subsequently, the 43S complex / rRNA modification in the nucleus and cytosol / erythrocyte homeostasis / cytoplasmic side of rough endoplasmic reticulum membrane / A band / laminin receptor activity / regulation of G1 to G0 transition / exit from mitosis / alpha-beta T cell differentiation / lysosomal transport / 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 kinase A binding / protein-DNA complex disassembly / positive regulation of DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / Translation initiation complex formation / Ribosomal scanning and start codon recognition / negative regulation of ubiquitin protein ligase activity / optic nerve development / ion channel inhibitor activity / pigmentation / low-density lipoprotein particle receptor binding / mammalian oogenesis stage / positive regulation of mitochondrial depolarization / response to aldosterone / retinal ganglion cell axon guidance / G1 to G0 transition / triglyceride metabolic process / homeostatic process / activation-induced cell death of T cells / lung morphogenesis / negative regulation of Wnt signaling pathway / fibroblast growth factor binding / positive regulation of T cell receptor signaling pathway / positive regulation of activated T cell proliferation / iron-sulfur cluster binding / COPII-coated ER to Golgi transport vesicle / regulation of cell division / Protein hydroxylation / negative regulation of peptidyl-serine phosphorylation Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.72 Å | |||||||||
Authors | Li W / Cate JHD | |||||||||
Funding support | United States, 1 items
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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 | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_0597.map.gz | 283.7 MB | EMDB map data format | |
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Header (meta data) | emd-0597-v30.xml emd-0597.xml | 16.7 KB 16.7 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_0597_fsc.xml | 15.2 KB | Display | FSC data file |
Images | emd_0597.png | 170.1 KB | ||
Others | emd_0597_additional.map.gz emd_0597_half_map_1.map.gz emd_0597_half_map_2.map.gz | 242.1 MB 242 MB 241.8 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-0597 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-0597 | HTTPS FTP |
-Validation report
Summary document | emd_0597_validation.pdf.gz | 679.3 KB | Display | EMDB validaton report |
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Full document | emd_0597_full_validation.pdf.gz | 678.9 KB | Display | |
Data in XML | emd_0597_validation.xml.gz | 20.6 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-0597 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-0597 | HTTPS FTP |
-Related structure data
Related structure data | 6om7MC 0526C 0596C 0598C 0599C 0600C 0601C 6oleC 6olfC 6olgC 6oliC 6olzC 6om0C C: citing same article (ref.) M: atomic model generated by this map |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_0597.map.gz / Format: CCP4 / Size: 303.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | PF846 stalled human ribosome nascent chain complex (PCSK9-RNC) in rotated state with AA tRNA and PE tRNA; map is sharpened. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.22 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Additional map: PF846 stalled human ribosome nascent chain complex (PCSK9-RNC)...
File | emd_0597_additional.map | ||||||||||||
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Annotation | PF846 stalled human ribosome nascent chain complex (PCSK9-RNC) in rotated state with AA tRNA and PE tRNA, map is not sharpened. | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half map of PF846 stalled human ribosome nascent...
File | emd_0597_half_map_1.map | ||||||||||||
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Annotation | Half map of PF846 stalled human ribosome nascent chain complex (PCSK9-RNC) in rotated state with AA tRNA and PE tRNA. | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half map of PF846 stalled human ribosome nascent...
File | emd_0597_half_map_2.map | ||||||||||||
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Annotation | Half map of PF846 stalled human ribosome nascent chain complex (PCSK9-RNC) in rotated state with AA tRNA and PE tRNA. | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Drug-like molecule PF846 stalled human ribosome nascent chain com...
Entire | Name: Drug-like molecule PF846 stalled human ribosome nascent chain complex, PCSK9-RNC in rotated state with AA tRNA and PE tRNA |
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Components |
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-Supramolecule #1: Drug-like molecule PF846 stalled human ribosome nascent chain com...
Supramolecule | Name: Drug-like molecule PF846 stalled human ribosome nascent chain complex, PCSK9-RNC in rotated state with AA tRNA and PE tRNA type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Homo sapiens (human) / Recombinant cell: HeLa |
Molecular weight | Theoretical: 4.3 MDa |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.8 |
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Grid | Details: unspecified |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 4 K |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
-Atomic model buiding 1
Refinement | Space: REAL / Overall B value: 91 |
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Output model | PDB-6om7: |