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- EMDB-0526: Structure of drug-like molecule stalled USO1 ribosome nascent cha... -

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Entry
Database: EMDB / ID: EMD-0526
TitleStructure of drug-like molecule stalled USO1 ribosome nascent chain complex (human)
Map data
SampleDrug-like molecule PF846 stalled human ribosome nascent chain complex, USO1-RNC:
nucleic-acidNucleic acid
Function / homology
Function and homology information


negative regulation of formation of translation preinitiation complex / positive regulation of selenocysteine incorporation / negative regulation of protein neddylation / TORC2 complex binding / response to antineoplastic agent / eukaryotic 80S initiation complex / positive regulation of signal transduction by p53 class mediator / embryonic brain development / protein-DNA complex disassembly / ribosomal protein import into nucleus ...negative regulation of formation of translation preinitiation complex / positive regulation of selenocysteine incorporation / negative regulation of protein neddylation / TORC2 complex binding / response to antineoplastic agent / eukaryotic 80S initiation complex / positive regulation of signal transduction by p53 class mediator / embryonic brain development / protein-DNA complex disassembly / ribosomal protein import into nucleus / axial mesoderm development / positive regulation of DNA N-glycosylase activity / positive regulation of base-excision repair / response to TNF agonist / oxidized pyrimidine DNA binding / negative regulation of DNA repair / positive regulation of respiratory burst involved in inflammatory response / positive regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis / 90S preribosome assembly / nucleolus organization / selenocysteine insertion sequence binding / protein tyrosine kinase inhibitor activity / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage / positive regulation of gastrulation / GAIT complex / response to extracellular stimulus / positive regulation of Golgi to plasma membrane protein transport / NF-kappaB complex / IRE1-RACK1-PP2A complex / negative regulation of RNA splicing / ubiquitin ligase inhibitor activity / laminin receptor activity / cytoplasmic side of rough endoplasmic reticulum membrane / response to insecticide / response to aldosterone / positive regulation of endodeoxyribonuclease activity / oxidized purine DNA binding / regulation of cell division / protein kinase A binding / negative regulation of endoplasmic reticulum unfolded protein response / 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 / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / middle ear morphogenesis / supercoiled DNA binding / negative regulation of ubiquitin protein ligase activity / negative regulation of hydrogen peroxide-induced neuron death / positive regulation of ceramide biosynthetic process / signaling adaptor activity / erythrocyte homeostasis / negative regulation of phagocytosis / ubiquitin-like protein conjugating enzyme binding / cytosolic ribosome / regulation of establishment of cell polarity / negative regulation of Wnt signaling pathway / pigmentation / cysteine-type endopeptidase activator activity involved in apoptotic process / positive regulation of T cell receptor signaling pathway / endonucleolytic cleavage to generate mature 3'-end of SSU-rRNA from (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / positive regulation of mitochondrial depolarization / translation regulator activity / phagocytic cup / rescue of stalled ribosome / class I DNA-(apurinic or apyrimidinic site) endonuclease activity / bone development / positive regulation of activated T cell proliferation / ribonucleoprotein complex assembly / positive regulation of cellular component movement / fibroblast growth factor binding / iron-sulfur cluster binding / ion channel inhibitor activity / stress granule assembly / poly(U) RNA binding / positive regulation of apoptotic signaling pathway / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / 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) / DNA-(apurinic or apyrimidinic site) lyase / positive regulation of interleukin-2 production / monocyte chemotaxis / positive regulation of ubiquitin-protein transferase activity / BH3 domain binding / positive regulation of cyclic-nucleotide phosphodiesterase activity / spindle assembly / negative regulation of proteasomal ubiquitin-dependent protein catabolic process / ribosomal small subunit export from nucleus / SRP-dependent cotranslational protein targeting to membrane / maturation of SSU-rRNA / regulation of translational fidelity / TOR signaling / protein localization to nucleus / negative regulation of protein kinase B signaling / positive regulation of JUN kinase activity / regulation of tumor necrosis factor-mediated signaling pathway / small-subunit processome / cellular response to actinomycin D / negative regulation of ubiquitin-dependent protein catabolic process / gastrulation / maturation of LSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / negative regulation of respiratory burst involved in inflammatory response / polysome
Ribosomal protein S28e / 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 S28e / 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 L13, eukaryotic/archaeal / Ribosomal protein S10, eukaryotic/archaeal / Ribosomal protein L22/L17, eukaryotic/archaeal / Ribosomal protein S5/S7, eukaryotic/archaeal / Ribosomal protein S19A/S15e / Ribosomal protein S5, eukaryotic/archaeal / Ribosomal protein S4/S9, eukaryotic/archaeal / Ribosomal protein S2, eukaryotic/archaeal / Ribosomal protein S3, eukaryotic/archaeal / Ribosomal protein S23, eukaryotic/archaeal / Ribosomal protein L23/L25, N-terminal / Ribosomal protein L6, N-terminal / Ribosomal protein L5 eukaryotic/L18 archaeal / Plectin/S10, N-terminal / Zinc-binding ribosomal protein / Ribosomal protein S13/S15, N-terminal / Ribosomal protein S25 / WD40-repeat-containing domain / Ribosomal protein L27e, conserved site / Ribosomal protein L22/L17, conserved site / Ribosomal protein L21e, conserved site / Ribosomal protein L13e, conserved site / Ribosomal protein L10e, conserved site / Ribosomal protein L29, conserved site / Ribosomal protein S4e, N-terminal, conserved site / Ribosomal protein S5, N-terminal, conserved site / Ribosomal protein S2, conserved site / Ribosomal S11, conserved site / Ribosomal S24e conserved site / Ribosomal protein S4, conserved site / Ribosomal protein L34e, 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 L3 / 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 / Ribosomal protein S5, C-terminal / K Homology domain, type 2 / Ribosomal protein L35Ae, conserved site / Ribosomal protein S8 / Ribosomal protein L10e / Ribosomal protein L15, conserved site / Ribosomal protein L21e / Ribosomal protein L27e / Ribosomal protein L22/L17 / Ribosomal protein S8e / Ribosomal protein L23/L25, conserved site / Ribosomal protein L24e-related / 60S ribosomal protein L6E / Ribosomal protein S26e / Ribosomal protein S4e / Ribosomal protein S5 / Ribosomal protein S9 / Ribosomal protein L6 / Ribosomal protein L18e / Ribosomal protein S17e / Ribosomal protein L31e / Ribosomal protein L39e / Ribosomal protein L19/L19e / Ribosomal protein L14P / Ribosomal protein L30e / Ribosomal protein S5/S7 / Ribosomal protein S17/S11 / Ubiquitin-like domain / Ribosomal protein L15e / Ribosomal protein L36e / Ribosomal protein S12e / Ribosomal protein L44e / Ribosomal protein S7e
40S ribosomal protein S26 / 40S ribosomal protein S25 / 40S ribosomal protein S24 / 40S ribosomal protein S28 / 40S ribosomal protein S15 / 60S ribosomal protein L23 / 40S ribosomal protein S29 / 40S ribosomal protein S6 / 60S ribosomal protein L23a / 40S ribosomal protein S4, X isoform ...40S ribosomal protein S26 / 40S ribosomal protein S25 / 40S ribosomal protein S24 / 40S ribosomal protein S28 / 40S ribosomal protein S15 / 60S ribosomal protein L23 / 40S ribosomal protein S29 / 40S ribosomal protein S6 / 60S ribosomal protein L23a / 40S ribosomal protein S4, X isoform / 60S ribosomal protein L7a / 40S ribosomal protein S11 / 40S ribosomal protein S13 / 60S ribosomal protein L30 / 40S ribosomal protein S18 / 40S ribosomal protein S23 / 40S ribosomal protein S30 / Ubiquitin-60S ribosomal protein L40 / 60S ribosomal protein L39 / 60S ribosomal protein L24 / 40S ribosomal protein S16 / 60S ribosomal protein L23 / 60S ribosomal protein L18 / 60S ribosomal protein L6 / 60S ribosomal protein L18a / 60S ribosomal protein L19 / 60S ribosomal protein L36a / Receptor of activated protein C kinase 1 / 60S ribosomal protein L31 / 40S ribosomal protein S21 / 60S ribosomal protein L38 / Ubiquitin-40S ribosomal protein S27a / 60S ribosomal protein L41 / 60S ribosomal protein L8 / 60S ribosomal protein L11 / 60S ribosomal protein L32 / 40S ribosomal protein S14 / 40S ribosomal protein S12 / 40S ribosomal protein S15a / 60S ribosomal protein L13 / 60S ribosomal protein L13a / 60S ribosomal protein L3 / 40S ribosomal protein S19 / 60S ribosomal protein L4 / 60S ribosomal protein L22 / 60S ribosomal protein L9 / 60S ribosomal protein L10 / 40S ribosomal protein S3 / 60S ribosomal protein L35 / 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 / 40S ribosomal protein S27 / 60S ribosomal protein L27a / 40S ribosomal protein S8 / 40S ribosomal protein S20 / 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 S3a / 60S ribosomal protein L14 / 60S ribosomal protein L5 / 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 L21 / 60S ribosomal protein L36
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsLi W / Cate JHD
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research InstituteR01-GM065050 United States
CitationJournal: 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.
Validation ReportPDB-ID: 6oli

SummaryFull reportAbout validation report
History
DepositionFeb 6, 2019-
Header (metadata) releaseMar 6, 2019-
Map releaseJun 5, 2019-
UpdateJun 19, 2019-
Current statusJun 19, 2019Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.021
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.021
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6oli
  • Surface level: 0.021
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
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Supplemental images

Downloads & links

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Map

FileDownload / File: emd_0526.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.15 Å/pix.
x 400 pix.
= 460. Å
1.15 Å/pix.
x 400 pix.
= 460. Å
1.15 Å/pix.
x 400 pix.
= 460. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.15 Å
Density
Contour LevelBy AUTHOR: 0.021 / Movie #1: 0.021
Minimum - Maximum-0.052317448 - 0.10637717
Average (Standard dev.)0.00046923864 (±0.0061468002)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 460.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.151.151.15
M x/y/z400400400
origin x/y/z0.0000.0000.000
length x/y/z460.000460.000460.000
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS400400400
D min/max/mean-0.0520.1060.000

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Supplemental data

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Sample components

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Entire Drug-like molecule PF846 stalled human ribosome nascent chain com...

EntireName: Drug-like molecule PF846 stalled human ribosome nascent chain complex, USO1-RNC
Number of components: 2

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Component #1: protein, Drug-like molecule PF846 stalled human ribosome nascent ...

ProteinName: Drug-like molecule PF846 stalled human ribosome nascent chain complex, USO1-RNC
Recombinant expression: No
MassTheoretical: 4.3 MDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human) / Cell of expression system: HeLa

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Component #2: nucleic-acid, Drug-like molecule PF846 stalled human ribosome nas...

nucleic acidName: Drug-like molecule PF846 stalled human ribosome nascent chain complex, USO1-RNC
Class: RNA / Structure: OTHER / Synthetic: No
Sequence:
RMKPWFEVGD ENSGWSAQKV TNLHLMLQLV RVLVSPTNPP GA
SourceSpecies: Homo sapiens (human)

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionpH: 7.8
Support filmunspecified
VitrificationCryogen name: ETHANE / Temperature: 4 K / 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: 55 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: 38314
3D reconstructionResolution: 3.5 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: 91
Output model

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