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- EMDB-0598: Structure of a drug-like molecule stalled ribosome nascent chain ... -
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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-0598 | |||||||||
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Title | Structure of a drug-like molecule stalled ribosome nascent chain complex (PCSK9_RNC) in non-rotated state with PP tRNA | |||||||||
![]() | PF846 stalled human ribosome nascent chain complex (PCSK9-RNC) in non-rotated state with PP tRNA. Map is sharpened. | |||||||||
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Function / homology | ![]() 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 / eukaryotic 80S initiation complex / very-low-density lipoprotein particle receptor binding / 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 / negative regulation of low-density lipoprotein receptor activity / 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 / negative regulation of receptor internalization / endolysosome membrane / negative regulation of DNA repair / negative regulation of RNA splicing / 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 / middle ear morphogenesis / NF-kappaB complex / 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 / lysosomal transport / 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 / 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 / triglyceride metabolic process / low-density lipoprotein particle receptor binding / 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 / homeostatic process / 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 / COPII-coated ER to Golgi transport vesicle / fibroblast growth factor binding / positive regulation of activated T cell proliferation / iron-sulfur cluster binding / regulation of cell division / Protein hydroxylation / monocyte chemotaxis Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.9 Å | |||||||||
![]() | Li W / Cate JHD | |||||||||
Funding support | ![]()
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![]() | ![]() 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
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 229 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 17.2 KB 17.2 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 14.2 KB | Display | ![]() |
Images | ![]() | 163.5 KB | ||
Others | ![]() ![]() ![]() | 193.1 MB 193.8 MB 193.8 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 6olzMC ![]() 0526C ![]() 0596C ![]() 0597C ![]() 0599C ![]() 0600C ![]() 0601C ![]() 6oleC ![]() 6olfC ![]() 6olgC ![]() 6oliC ![]() 6om0C ![]() 6om7C C: citing same article ( M: atomic model generated by this map |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | PF846 stalled human ribosome nascent chain complex (PCSK9-RNC) in non-rotated state with PP 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_0598_additional.map | ||||||||||||
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Annotation | PF846 stalled human ribosome nascent chain complex (PCSK9-RNC) in non-rotated state with PP 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_0598_half_map_1.map | ||||||||||||
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Annotation | Half map of PF846 stalled human ribosome nascent chain complex (PCSK9-RNC) in non-rotated state with PP tRNA. | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half map of PF846 stalled human ribosome nascent...
File | emd_0598_half_map_2.map | ||||||||||||
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Annotation | Half map of PF846 stalled human ribosome nascent chain complex (PCSK9-RNC) in non-rotated state with PP tRNA. | ||||||||||||
Projections & Slices |
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Density Histograms |
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Sample components
-Entire : Drug-like molecule stalled human ribosome nascent chain complex (...
Entire | Name: Drug-like molecule stalled human ribosome nascent chain complex (PCSK9-RNC) in non-rotated state with PP tRNA |
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Components |
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-Supramolecule #1: Drug-like molecule stalled human ribosome nascent chain complex (...
Supramolecule | Name: Drug-like molecule stalled human ribosome nascent chain complex (PCSK9-RNC) in non-rotated state with PP tRNA type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: ![]() |
Recombinant expression | Organism: ![]() |
Molecular weight | Theoretical: 4.3 MDa |
-Macromolecule #1: human ribosome with nascent chain
Macromolecule | Name: human ribosome with nascent chain / type: rna / ID: 1 Details: Nascent chain sequence including CDH1 domain V and PCSK9 1-35 |
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Source (natural) | Organism: ![]() |
Sequence | String: SDVNDNAPIP EPRTIFFCER NPKPQVINII DADLPPNTSP FTAELTHGAS ANWTIQYNDP TQESIILKPK MALEVGDYKI NLKLMDNQNK DQVTTLEVSV CDCEGAAGVC RKAQPVEAGL QIPAILGILG MGTVSSRRS WWPLPLLLLL LLLLGPAGAR AQEDED |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.8 |
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Grid | Details: unspecified |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 4 K |
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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: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
-Atomic model buiding 1
Refinement | Space: REAL / Overall B value: 80 |
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Output model | ![]() PDB-6olz: |