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- EMDB-22086: Intermediate ribosome nascent chain complex during PF846 stalled ... -

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Entry
Database: EMDB / ID: EMD-22086
TitleIntermediate ribosome nascent chain complex during PF846 stalled translation termination
Map data
SampleTranslation termination complex stalled by a drug-like compound (intermediate state)
Function / homology
Function and homology information


translation termination factor activity / translation release factor complex / translation release factor activity / negative regulation of formation of translation preinitiation complex / positive regulation of selenocysteine incorporation / negative regulation of protein neddylation / cytoplasmic translational termination / TORC2 complex binding / response to antineoplastic agent / positive regulation of signal transduction by p53 class mediator ...translation termination factor activity / translation release factor complex / translation release factor activity / negative regulation of formation of translation preinitiation complex / positive regulation of selenocysteine incorporation / negative regulation of protein neddylation / cytoplasmic translational termination / TORC2 complex binding / response to antineoplastic agent / positive regulation of signal transduction by p53 class mediator / eukaryotic 80S initiation complex / ribosomal protein import into nucleus / protein-DNA complex disassembly / regulation of translational termination / axial mesoderm development / positive regulation of base-excision repair / negative regulation of DNA repair / positive regulation of DNA N-glycosylase activity / oxidized pyrimidine DNA binding / response to TNF agonist / selenocysteine insertion sequence binding / positive regulation of respiratory burst involved in inflammatory response / positive regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis / GAIT complex / nucleolus organization / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage / protein tyrosine kinase inhibitor activity / mammalian oogenesis stage / 90S preribosome assembly / positive regulation of gastrulation / NF-kappaB complex / positive regulation of Golgi to plasma membrane protein transport / IRE1-RACK1-PP2A complex / negative regulation of RNA splicing / response to extracellular stimulus / response to insecticide / translation release factor activity, codon specific / ubiquitin ligase inhibitor activity / laminin receptor activity / response to aldosterone / cytoplasmic side of rough endoplasmic reticulum membrane / positive regulation of endodeoxyribonuclease activity / regulation of cell division / oxidized purine DNA binding / activation-induced cell death of T cells / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / positive regulation of DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / regulation of translation involved in cellular response to UV / protein methylation / negative regulation of endoplasmic reticulum unfolded protein response / middle ear morphogenesis / supercoiled DNA binding / negative regulation of hydrogen peroxide-induced neuron death / protein kinase A binding / positive regulation of ceramide biosynthetic process / negative regulation of ubiquitin protein ligase activity / erythrocyte homeostasis / negative regulation of phagocytosis / signaling adaptor activity / ubiquitin-like protein conjugating enzyme binding / cytosolic ribosome / regulation of establishment of cell polarity / negative regulation of Wnt signaling pathway / translation regulator activity / pigmentation / sequence-specific mRNA binding / cysteine-type endopeptidase activator activity involved in apoptotic process / positive regulation of T cell receptor signaling pathway / positive regulation of mitochondrial depolarization / phagocytic cup / endonucleolytic cleavage to generate mature 3'-end of SSU-rRNA from (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / bone development / ion channel inhibitor activity / positive regulation of activated T cell proliferation / erythrocyte development / rescue of stalled ribosome / ribonucleoprotein complex assembly / positive regulation of cellular component movement / fibroblast growth factor binding / iron-sulfur cluster binding / positive regulation of apoptotic signaling pathway / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / stress granule assembly / DNA-(apurinic or apyrimidinic site) lyase / monocyte chemotaxis / T cell proliferation involved in immune response / class I DNA-(apurinic or apyrimidinic site) endonuclease activity / positive regulation of ubiquitin-protein transferase activity / BH3 domain binding / negative regulation of proteasomal ubiquitin-dependent protein catabolic process / endonucleolytic cleavage in ITS1 to separate SSU-rRNA from 5.8S rRNA and LSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / positive regulation of cyclic-nucleotide phosphodiesterase activity / spindle assembly / positive regulation of JUN kinase activity / TOR signaling / regulation of tumor necrosis factor-mediated signaling pathway / ribosomal small subunit export from nucleus / SRP-dependent cotranslational protein targeting to membrane / positive regulation of interleukin-2 production / negative regulation of protein kinase B signaling
Ribosomal protein L19/L19e / Ribosomal protein L13 / Ribosomal protein L37ae/L37e / TRASH domain / Ribosomal protein S13-like, H2TH / S15/NS1, RNA-binding / K homology domain superfamily, prokaryotic type / Translation protein, beta-barrel domain superfamily / Translation protein SH3-like domain superfamily / Ribosomal protein L34Ae ...Ribosomal protein L19/L19e / Ribosomal protein L13 / Ribosomal protein L37ae/L37e / TRASH domain / Ribosomal protein S13-like, H2TH / S15/NS1, RNA-binding / K homology domain superfamily, prokaryotic type / Translation protein, beta-barrel domain superfamily / Translation protein SH3-like domain superfamily / Ribosomal protein L34Ae / Ribosomal protein L41 / Ribosomal protein S30 / Ribosomal protein S12/S23 / Ribosomal protein L7, eukaryotic / Ribosomal protein L24/L26, conserved site / KOW / Ribosomal protein L26/L24, eukaryotic/archaeal / Nucleic acid-binding, OB-fold / Ribosomal protein S3, eukaryotic/archaeal / Ribosomal protein S5, C-terminal / Plectin/S10, N-terminal / Ribosomal protein L5 eukaryotic/L18 archaeal / Ribosomal protein L6, N-terminal / Ribosomal protein L23/L25, N-terminal / Ribosomal protein S23, eukaryotic/archaeal / Ribosomal protein S2, eukaryotic/archaeal / Ribosomal protein L13, eukaryotic/archaeal / Ribosomal protein S4/S9, eukaryotic/archaeal / Ribosomal protein S5, eukaryotic/archaeal / Ribosomal protein S19A/S15e / Ribosomal protein S5/S7, eukaryotic/archaeal / Ribosomal protein L22/L17, eukaryotic/archaeal / Ribosomal protein S10, eukaryotic/archaeal / Zinc-binding ribosomal protein / Ribosomal protein S13/S15, N-terminal / eRF1 domain 2 / Ribosomal protein S4e, N-terminal, conserved site / Ribosomal protein L34e, conserved site / Ribosomal protein S4, conserved site / Ribosomal S24e conserved site / Ribosomal S11, conserved site / Ribosomal protein S2, conserved site / Ribosomal protein S5, N-terminal, conserved site / Ribosomal protein L29, conserved site / WD40-repeat-containing domain / Ribosomal protein L10e, conserved site / Ribosomal protein L13e, conserved site / Ribosomal protein L21e, conserved site / Ribosomal protein L22/L17, conserved site / Ribosomal protein L27e, conserved site / Ribosomal protein L32e, conserved site / Ribosomal protein L30, conserved site / Ribosomal protein L10e/L16 / Nucleotide-binding alpha-beta plait domain superfamily / Ribosomal protein S4e, central region / Ribosomal protein L23/L15e core domain superfamily / Ribosomal protein L30, N-terminal / Ribosomal protein L4/L1e, eukaryotic/archaeal, conserved site / Ribosomal protein L25/L23 / Ribosomal protein S5, N-terminal / Ribosomal protein S4e, N-terminal / Ribosomal protein S15 / Ribosomal protein L30, ferredoxin-like fold domain / Ribosomal protein S5 domain 2-type fold, subgroup / Ribosomal protein L2, domain 2 / Ribosomal protein L2, domain 3 / WD40/YVTN repeat-like-containing domain superfamily / K homology domain-like, alpha/beta / Ribosomal protein L19/L19e, domain 1 / eRF1 domain 3 / eRF1 domain 1/Pelota-like / Ribosomal protein L37e, conserved site / Ribosomal protein S8e / Ribosomal protein S5 / Ribosomal protein S4e / Ribosomal protein S26e / 60S ribosomal protein L6E / Ribosomal protein L24e-related / Ribosomal protein L23/L25, conserved site / Ribosomal protein L22/L17 / Ribosomal protein L6 / Ribosomal protein L27e / Ribosomal protein L21e / Ribosomal protein L15, conserved site / Ribosomal protein L10e / Ribosomal protein S14 / Ribosomal protein S17e / Ribosomal protein S9 / Ribosomal protein S8 / Ribosomal protein S3, C-terminal / Ribosomal protein S5/S7 / Ribosomal protein L44e / Ribosomal protein S12e / Ribosomal protein L36e / Ribosomal protein L15e / Ribosomal protein S28e / Ribosomal protein S17/S11 / Ribosomal protein L30e / Ubiquitin-like domain / Ribosomal protein L14P
40S ribosomal protein S29 / 60S ribosomal protein L39 / 40S ribosomal protein S18 / 40S ribosomal protein S28 / 40S ribosomal protein S26 / 40S ribosomal protein S25 / 40S ribosomal protein S24 / 40S ribosomal protein S15 / 60S ribosomal protein L23 / 40S ribosomal protein S13 ...40S ribosomal protein S29 / 60S ribosomal protein L39 / 40S ribosomal protein S18 / 40S ribosomal protein S28 / 40S ribosomal protein S26 / 40S ribosomal protein S25 / 40S ribosomal protein S24 / 40S ribosomal protein S15 / 60S ribosomal protein L23 / 40S ribosomal protein S13 / 40S ribosomal protein S6 / 60S ribosomal protein L23a / 40S ribosomal protein S4, X isoform / Eukaryotic peptide chain release factor subunit 1 / 60S ribosomal protein L7a / 40S ribosomal protein S11 / 60S ribosomal protein L30 / 40S ribosomal protein S21 / 60S ribosomal protein L31 / 60S ribosomal protein L36a / 40S ribosomal protein S14 / 60S ribosomal protein L10-like / Heparin-binding protein HBp15 / 60S ribosomal protein L18 / 60S ribosomal protein L6 / 60S ribosomal protein L18a / 60S ribosomal protein L19 / 60S ribosomal protein L24 / 60S ribosomal protein L32 / Receptor of activated protein C kinase 1 / 60S ribosomal protein L38 / Ubiquitin-60S ribosomal protein L40 / Ubiquitin-40S ribosomal protein S27a / 60S ribosomal protein L41 / 60S ribosomal protein L8 / 60S ribosomal protein L11 / 40S ribosomal protein S23 / 40S ribosomal protein S27 / 40S ribosomal protein S16 / 40S ribosomal protein S12 / 60S ribosomal protein L13a / 60S ribosomal protein L3 / 40S ribosomal protein S19 / 60S ribosomal protein L4 / 60S ribosomal protein L9 / 60S ribosomal protein L13 / 40S ribosomal protein S3 / 60S ribosomal protein L27a / 60S ribosomal protein L17 / 60S ribosomal protein L7 / 60S ribosomal protein L35a / 40S ribosomal protein S2 / 40S ribosomal protein SA / 40S ribosomal protein S17 / 40S ribosomal protein S30 / 60S ribosomal protein L35 / 60S ribosomal protein L5 / 40S ribosomal protein S15a / 40S ribosomal protein S3a / 40S ribosomal protein S8 / 40S ribosomal protein S7 / 60S ribosomal protein L37 / 60S ribosomal protein L37a / 60S ribosomal protein L27 / 60S ribosomal protein L15 / 60S ribosomal protein L26 / 40S ribosomal protein S20 / 60S ribosomal protein L21 / 60S ribosomal protein L14 / 60S ribosomal protein L34 / 60S ribosomal protein L29 / 40S ribosomal protein S10 / 40S ribosomal protein S5 / 40S ribosomal protein S9 / 60S ribosomal protein L28 / 60S ribosomal protein L36
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsLi W / Cate J / Ward RF / Chang S
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01- GM065050 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01-GM131142 United States
CitationJournal: Nat Commun / Year: 2020
Title: Selective inhibition of human translation termination by a drug-like compound.
Authors: Wenfei Li / Stacey Tsai-Lan Chang / Fred R Ward / Jamie H D Cate /
Abstract: Methods to directly inhibit gene expression using small molecules hold promise for the development of new therapeutics targeting proteins that have evaded previous attempts at drug discovery. Among ...Methods to directly inhibit gene expression using small molecules hold promise for the development of new therapeutics targeting proteins that have evaded previous attempts at drug discovery. Among these, small molecules including the drug-like compound PF-06446846 (PF846) selectively inhibit the synthesis of specific proteins, by stalling translation elongation. These molecules also inhibit translation termination by an unknown mechanism. Using cryo-electron microscopy (cryo-EM) and biochemical approaches, we show that PF846 inhibits translation termination by arresting the nascent chain (NC) in the ribosome exit tunnel. The arrested NC adopts a compact α-helical conformation that induces 28 S rRNA nucleotide rearrangements that suppress the peptidyl transferase center (PTC) catalytic activity stimulated by eukaryotic release factor 1 (eRF1). These data support a mechanism of action for a small molecule targeting translation that suppresses peptidyl-tRNA hydrolysis promoted by eRF1, revealing principles of eukaryotic translation termination and laying the foundation for new therapeutic strategies.
History
DepositionMay 30, 2020-
Header (metadata) releaseOct 14, 2020-
Map releaseOct 14, 2020-
UpdateOct 14, 2020-
Current statusOct 14, 2020Processing site: RCSB / Status: Released

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Structure visualization

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  • Surface view with section colored by density value
  • Surface level: 0.02
  • Imaged by UCSF Chimera
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  • Surface level: 0.02
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Structure viewerEM map:
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Map

FileDownload / File: emd_22086.map.gz / Format: CCP4 / Size: 303.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.15 Å/pix.
x 430 pix.
= 494.5 Å
1.15 Å/pix.
x 430 pix.
= 494.5 Å
1.15 Å/pix.
x 430 pix.
= 494.5 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.15 Å
Density
Contour LevelBy AUTHOR: 0.02 / Movie #1: 0.02
Minimum - Maximum-0.02401054 - 0.11571237
Average (Standard dev.)0.00015594714 (±0.005483045)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions430430430
Spacing430430430
CellA=B=C: 494.5 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.151.151.15
M x/y/z430430430
origin x/y/z0.0000.0000.000
length x/y/z494.500494.500494.500
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ360360360
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS430430430
D min/max/mean-0.0240.1160.000

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Supplemental data

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Segmentation: #1

Fileemd_22086_msk_1.map
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Additional map: overall refined map without B factor sharpening

Fileemd_22086_additional_1.map
Annotationoverall refined map without B factor sharpening
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Half map: half map

Fileemd_22086_half_map_1.map
Annotationhalf map
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Half map: half map

Fileemd_22086_half_map_2.map
Annotationhalf map
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Sample components

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Entire Translation termination complex stalled by a drug-like compound (...

EntireName: Translation termination complex stalled by a drug-like compound (intermediate state)
Number of components: 1

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Component #1: protein, Translation termination complex stalled by a drug-like c...

ProteinName: Translation termination complex stalled by a drug-like compound (intermediate state)
Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionpH: 7.6
Support filmunspecified
VitrificationCryogen name: ETHANE / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 50 e/Å2 / Illumination mode: FLOOD BEAM
LensImaging mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: GATAN K2 SUMMIT (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Number of projections: 26463
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF
FSC plot (resolution estimation)

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Atomic model buiding

Modeling #1Refinement space: REAL / Overall bvalue: 50

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