|Entry||Database: EMDB / ID: EMD-20134|
|Title||Structure of a drug-like molecule stalled PCSK9 ribosome nascent chain complex (PCSK9-RNC) with AP tRNA and PE tRNA (sample prepared with a short incubation time)|
|Sample||Structure of a drug-like molecule stalled PCSK9 ribosome nascent chain complex (PCSK9-RNC) with AP tRNA and PE tRNA (sample prepared with a short incubation time)|
|Biological species||Homo sapiens (human)|
|Method||single particle reconstruction / cryo EM / Resolution: 4.7 Å|
|Authors||Li W / Cate JHD|
|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.
|Date||Deposition: Apr 19, 2019 / Header (metadata) release: Jun 5, 2019 / Map release: Jun 5, 2019 / Update: Jun 19, 2019|
|Structure viewer||EM map: |
Downloads & links
|File||Download / File: emd_20134.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)|
|Projections & slices|
Images are generated by Spider.
|Voxel size||X=Y=Z: 1.22 Å|
|Symmetry||Space group: 1|
CCP4 map header:
-Entire Structure of a drug-like molecule stalled PCSK9 ribosome nascent ...
|Entire||Name: Structure of a drug-like molecule stalled PCSK9 ribosome nascent chain complex (PCSK9-RNC) with AP tRNA and PE tRNA (sample prepared with a short incubation time)|
Number of components: 1
-Component #1: protein, Structure of a drug-like molecule stalled PCSK9 ribosome...
|Protein||Name: Structure of a drug-like molecule stalled PCSK9 ribosome nascent chain complex (PCSK9-RNC) with AP tRNA and PE tRNA (sample prepared with a short incubation time)|
Recombinant expression: No
|Mass||Theoretical: 4.3 MDa|
|Source||Species: Homo sapiens (human)|
|Source (engineered)||Expression System: Homo sapiens (human) / Cell of expression system: HeLa|
|Specimen||Specimen state: Particle / Method: cryo EM|
|Sample solution||pH: 7.5|
|Vitrification||Cryogen name: ETHANE / Temperature: 4 K / Humidity: 100 %|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Imaging||Microscope: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 50 e/Å2 / Illumination mode: FLOOD BEAM|
|Lens||Imaging mode: BRIGHT FIELD|
|Specimen Holder||Model: OTHER|
|Camera||Detector: GATAN K2 SUMMIT (4k x 4k)|
|Processing||Method: single particle reconstruction / Number of projections: 8433|
|3D reconstruction||Resolution: 4.7 Å / Resolution method: FSC 0.143 CUT-OFF|
-Atomic model buiding
|Modeling #1||Refinement space: REAL / Overall bvalue: 75|
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