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

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Basic information

Entry
Database: EMDB / ID: EMD-0526
TitleStructure of drug-like molecule stalled USO1 ribosome nascent chain complex (human)
Map dataOverall map of PF846 stalled USO1-RNC(ribosome nascent chain complex)
Sample
  • Complex: Drug-like molecule PF846 stalled human ribosome nascent chain complex, USO1-RNC
    • RNA: Drug-like molecule PF846 stalled human ribosome nascent chain complex, USO1-RNC
Function / homology
Function and homology information


embryonic brain development / eukaryotic 80S initiation complex / negative regulation of protein neddylation / negative regulation of endoplasmic reticulum unfolded protein response / oxidized pyrimidine DNA binding / response to TNF agonist / positive regulation of base-excision repair / negative regulation of formation of translation preinitiation complex / regulation of G1 to G0 transition / axial mesoderm development ...embryonic brain development / eukaryotic 80S initiation complex / negative regulation of protein neddylation / negative regulation of endoplasmic reticulum unfolded protein response / oxidized pyrimidine DNA binding / response to TNF agonist / positive regulation of base-excision repair / negative regulation of formation of translation preinitiation complex / regulation of G1 to G0 transition / axial mesoderm development / ribosomal protein import into nucleus / positive regulation of respiratory burst involved in inflammatory response / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage / 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 / positive regulation of gastrulation / nucleolus organization / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / protein tyrosine kinase inhibitor activity / 90S preribosome assembly / : / IRE1-RACK1-PP2A complex / positive regulation of endodeoxyribonuclease activity / positive regulation of Golgi to plasma membrane protein transport / translation at postsynapse / TNFR1-mediated ceramide production / negative regulation of DNA repair / negative regulation of RNA splicing / TORC2 complex binding / mammalian oogenesis stage / GAIT complex / A band / supercoiled DNA binding / activation-induced cell death of T cells / G1 to G0 transition / oxidized purine DNA binding / NF-kappaB complex / neural crest cell differentiation / middle ear morphogenesis / negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide / alpha-beta T cell differentiation / ubiquitin-like protein conjugating enzyme binding / translation at presynapse / regulation of establishment of cell polarity / exit from mitosis / rRNA modification in the nucleus and cytosol / positive regulation of ubiquitin-protein transferase activity / negative regulation of phagocytosis / Formation of the ternary complex, and subsequently, the 43S complex / erythrocyte homeostasis / cytoplasmic side of rough endoplasmic reticulum membrane / laminin receptor activity / negative regulation of peptidyl-serine phosphorylation / protein kinase A binding / optic nerve development / negative regulation of ubiquitin protein ligase activity / pigmentation / retinal ganglion cell axon guidance / Ribosomal scanning and start codon recognition / ion channel inhibitor activity / response to aldosterone / Translation initiation complex formation / homeostatic process / positive regulation of mitochondrial depolarization / positive regulation of T cell receptor signaling pathway / macrophage chemotaxis / fibroblast growth factor binding / negative regulation of Wnt signaling pathway / lung morphogenesis / positive regulation of activated T cell proliferation / negative regulation of translational frameshifting / monocyte chemotaxis / Protein hydroxylation / BH3 domain binding / TOR signaling / cysteine-type endopeptidase activator activity involved in apoptotic process / SARS-CoV-1 modulates host translation machinery / regulation of cell division / iron-sulfur cluster binding / mTORC1-mediated signalling / T cell proliferation involved in immune response / Peptide chain elongation / Selenocysteine synthesis / positive regulation of signal transduction by p53 class mediator / endonucleolytic cleavage to generate mature 3'-end of SSU-rRNA from (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / Formation of a pool of free 40S subunits / ubiquitin ligase inhibitor activity / Eukaryotic Translation Termination / phagocytic cup / blastocyst development / Response of EIF2AK4 (GCN2) to amino acid deficiency / SRP-dependent cotranslational protein targeting to membrane / cellular response to actinomycin D / negative regulation of ubiquitin-dependent protein catabolic process / Viral mRNA Translation / negative regulation of respiratory burst involved in inflammatory response / Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) / protein localization to nucleus
Similarity search - Function
40S ribosomal protein SA / 40S ribosomal protein SA, C-terminal domain / 40S ribosomal protein SA C-terminus / Ribosomal protein L6, N-terminal / Ribosomal protein L6, N-terminal domain / Ubiquitin-like protein FUBI / Ribosomal protein L30e / Ribosomal protein L2, archaeal-type / Ribosomal L15/L27a, N-terminal / Ribosomal protein L28e ...40S ribosomal protein SA / 40S ribosomal protein SA, C-terminal domain / 40S ribosomal protein SA C-terminus / Ribosomal protein L6, N-terminal / Ribosomal protein L6, N-terminal domain / Ubiquitin-like protein FUBI / Ribosomal protein L30e / Ribosomal protein L2, archaeal-type / Ribosomal L15/L27a, N-terminal / Ribosomal protein L28e / Ribosomal protein L23 / Ribosomal L28e/Mak16 / Ribosomal L28e protein family / metallochaperone-like domain / TRASH domain / : / Ribosomal protein S26e signature. / Ribosomal protein L41 / Ribosomal protein L41 / Ribosomal protein S21e, conserved site / Ribosomal protein S21e signature. / Ribosomal protein S26e / Ribosomal protein S26e superfamily / Ribosomal protein S26e / : / Ribosomal protein S12e signature. / Ribosomal protein S12e / Ribosomal protein L29e / Ribosomal L29e protein family / Ribosomal protein S19e, conserved site / Ribosomal protein S19e signature. / Ribosomal protein L13e, conserved site / Ribosomal protein L13e signature. / Ribosomal protein S5, eukaryotic/archaeal / Ribosomal protein S21e / Ribosomal protein S21e superfamily / Ribosomal protein S21e / Ribosomal protein S2, eukaryotic / Small (40S) ribosomal subunit Asc1/RACK1 / Ribosomal protein L22e / Ribosomal protein L22e superfamily / Ribosomal L22e protein family / S27a-like superfamily / Ribosomal protein L38e / Ribosomal protein L38e superfamily / Ribosomal L38e protein family / 40S Ribosomal protein S10 / Ribosomal protein L27e, conserved site / Ribosomal protein L27e signature. / Ribosomal protein L10e, conserved site / Ribosomal protein L44e signature. / Ribosomal protein L10e signature. / Ribosomal protein L10e / Plectin/S10, N-terminal / Plectin/S10 domain / Ribosomal protein L19, eukaryotic / Ribosomal protein L13e / Ribosomal protein L13e / Ribosomal protein S10, eukaryotic/archaeal / Ribosomal protein S8e subdomain, eukaryotes / 60S ribosomal protein L18a/ L20, eukaryotes / : / Ribosomal protein L19/L19e conserved site / : / Ribosomal protein L19e signature. / Ribosomal protein S7e signature. / Ribosomal protein S25 / S25 ribosomal protein / Ribosomal protein S17e, conserved site / Ribosomal protein S17e signature. / Ribosomal protein L24e, conserved site / Ribosomal protein L24e signature. / Ribosomal protein L44e / Ribosomal protein L44 / Ribosomal protein S27a / : / Ribosomal protein S27a / Ribosomal protein S27a / Ribosomal protein L34e, conserved site / Ribosomal protein L34e signature. / Ribosomal protein S30 / Ribosomal protein S30 / Ribosomal protein S2, eukaryotic/archaeal / Ribosomal protein L5 eukaryotic, C-terminal / Ribosomal L18 C-terminal region / Ribosomal protein L6e signature. / Ribosomal protein L30e signature 1. / Ribosomal protein S3Ae, conserved site / Ribosomal protein S3Ae signature. / 50S ribosomal protein L18Ae/60S ribosomal protein L20 and L18a / Ribosomal protein 50S-L18Ae/60S-L20/60S-L18A / Ribosomal L40e family / Ribosomal proteins 50S-L18Ae/60S-L20/60S-L18A / 40S ribosomal protein S29/30S ribosomal protein S14 type Z / Ribosomal protein L23/L25, N-terminal / Ribosomal protein L23, N-terminal domain / 40S ribosomal protein S4, C-terminal domain / 40S ribosomal protein S4 C-terminus / Ribosomal protein S4e, N-terminal, conserved site / Ribosomal protein S4e signature.
Similarity search - Domain/homology
FAU ubiquitin like and ribosomal protein S30 fusion / Small ribosomal subunit protein eS17 / Small ribosomal subunit protein uS2 / Small ribosomal subunit protein uS5 / Large ribosomal subunit protein eL33 / Large ribosomal subunit protein uL30 / Large ribosomal subunit protein uL22 / Small ribosomal subunit protein uS3 / Small ribosomal subunit protein eS12 / Large ribosomal subunit protein eL13 ...FAU ubiquitin like and ribosomal protein S30 fusion / Small ribosomal subunit protein eS17 / Small ribosomal subunit protein uS2 / Small ribosomal subunit protein uS5 / Large ribosomal subunit protein eL33 / Large ribosomal subunit protein uL30 / Large ribosomal subunit protein uL22 / Small ribosomal subunit protein uS3 / Small ribosomal subunit protein eS12 / Large ribosomal subunit protein eL13 / Large ribosomal subunit protein uL16 / Large ribosomal subunit protein uL6 / Large ribosomal subunit protein eL22 / Large ribosomal subunit protein uL4 / Small ribosomal subunit protein eS19 / Large ribosomal subunit protein uL3 / Large ribosomal subunit protein uL13 / Small ribosomal subunit protein eS27 / Large ribosomal subunit protein uL29 / Large ribosomal subunit protein uL15 / Large ribosomal subunit protein uL18 / Large ribosomal subunit protein eL21 / Large ribosomal subunit protein eL28 / Small ribosomal subunit protein uS4 / Small ribosomal subunit protein uS7 / Small ribosomal subunit protein eS10 / Large ribosomal subunit protein eL29 / Large ribosomal subunit protein eL34 / Large ribosomal subunit protein eL14 / Small ribosomal subunit protein uS10 / Small ribosomal subunit protein eS1 / Large ribosomal subunit protein uL24 / Large ribosomal subunit protein eL15 / Large ribosomal subunit protein eL27 / Large ribosomal subunit protein eL43 / Large ribosomal subunit protein eL37 / Small ribosomal subunit protein eS7 / Small ribosomal subunit protein eS8 / Small ribosomal subunit protein uS8 / Small ribosomal subunit protein uS9 / Small ribosomal subunit protein uS11 / Small ribosomal subunit protein uS12 / Small ribosomal subunit protein uS13 / Small ribosomal subunit protein uS14 / Small ribosomal subunit protein uS15 / Small ribosomal subunit protein uS17 / Large ribosomal subunit protein eL8 / Small ribosomal subunit protein eS4, X isoform / Large ribosomal subunit protein uL23 / Small ribosomal subunit protein eS6 / Large ribosomal subunit protein uL14 / Small ribosomal subunit protein uS19 / Small ribosomal subunit protein eS24 / Small ribosomal subunit protein eS25 / Small ribosomal subunit protein eS26 / Small ribosomal subunit protein eS28 / Ubiquitin-like FUBI-ribosomal protein eS30 fusion protein / Large ribosomal subunit protein eL30 / Large ribosomal subunit protein eL39 / Large ribosomal subunit protein eL31 / Large ribosomal subunit protein eL32 / Large ribosomal subunit protein uL5 / Large ribosomal subunit protein uL2 / Small ribosomal subunit protein eS32 / Ubiquitin-ribosomal protein eS31 fusion protein / Ubiquitin-ribosomal protein eL40 fusion protein / Large ribosomal subunit protein eL38 / Small ribosomal subunit protein eS21 / Small ribosomal subunit protein RACK1 / Large ribosomal subunit protein eL24 / Large ribosomal subunit protein eL42 / Large ribosomal subunit protein eL19 / Large ribosomal subunit protein eL20 / Large ribosomal subunit protein eL6 / Large ribosomal subunit protein eL18 / Large ribosomal subunit protein uL14 / Large ribosomal subunit protein eL36
Similarity search - Component
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.
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:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_0526.png

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)
AnnotationOverall map of PF846 stalled USO1-RNC(ribosome nascent chain complex)
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

Histogram

Histogram (log scale)
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
Components
  • Complex: Drug-like molecule PF846 stalled human ribosome nascent chain complex, USO1-RNC
    • RNA: Drug-like molecule PF846 stalled human ribosome nascent chain complex, USO1-RNC

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Supramolecule #1: Drug-like molecule PF846 stalled human ribosome nascent chain com...

SupramoleculeName: Drug-like molecule PF846 stalled human ribosome nascent chain complex, USO1-RNC
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HeLa
Molecular weightTheoretical: 4.3 MDa

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Macromolecule #1: Drug-like molecule PF846 stalled human ribosome nascent chain com...

MacromoleculeName: Drug-like molecule PF846 stalled human ribosome nascent chain complex, USO1-RNC
type: rna / ID: 1
Source (natural)Organism: Homo sapiens (human)
SequenceString:
RMKPWFEVGD ENSGWSAQKV TNLHLMLQLV RVLVSPTNPP GA

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.8
GridPretreatment - Type: GLOW DISCHARGE / Details: unspecified
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 4 K

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 55.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 38314
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Overall B value: 91
Output model

PDB-6oli:
Structure of human ribosome nascent chain complex selectively stalled by a drug-like small molecule (USO1-RNC)

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