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- EMDB-0600: Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug... -

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Entry
Database: EMDB / ID: EMD-0600
TitleHuman ribosome nascent chain complex (CDH1-RNC) stalled by a drug-like molecule with AP tRNA and PE tRNA
Map data
SampleHuman ribosome nascent chain complex (CDH1-RNC) stalled by a drug-like molecule with AP tRNA and PE tRNA
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 / embryonic brain development / positive regulation of signal transduction by p53 class mediator / eukaryotic 80S initiation complex / 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 / embryonic brain development / positive regulation of signal transduction by p53 class mediator / eukaryotic 80S initiation complex / protein-DNA complex disassembly / ribosomal protein import into nucleus / axial mesoderm development / negative regulation of DNA repair / positive regulation of base-excision repair / response to TNF agonist / positive regulation of DNA N-glycosylase activity / oxidized pyrimidine DNA binding / positive regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis / positive regulation of respiratory burst involved in inflammatory response / 90S preribosome assembly / nucleolus organization / selenocysteine insertion sequence binding / cellular response to indole-3-methanol / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage / protein tyrosine kinase inhibitor activity / positive regulation of gastrulation / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / GAIT complex / response to extracellular stimulus / gamma-catenin binding / NF-kappaB complex / positive regulation of Golgi to plasma membrane protein transport / IRE1-RACK1-PP2A complex / negative regulation of RNA splicing / ubiquitin ligase inhibitor activity / pituitary gland development / flotillin complex / laminin receptor activity / cytoplasmic side of rough endoplasmic reticulum membrane / cell-cell adhesion mediated by cadherin / response to insecticide / response to aldosterone / positive regulation of endodeoxyribonuclease activity / oxidized purine DNA binding / regulation of cell division / calcium-dependent cell-cell adhesion via plasma membrane cell adhesion molecules / protein kinase A binding / negative regulation of endoplasmic reticulum unfolded protein response / regulation of translation involved in cellular response to UV / positive regulation of DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / 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 / cellular response to lithium ion / ubiquitin-like protein conjugating enzyme binding / cell-cell adhesion via plasma-membrane adhesion molecules / catenin complex / cytosolic ribosome / regulation of establishment of cell polarity / ankyrin binding / negative regulation of Wnt signaling pathway / pigmentation / apical junction complex / cysteine-type endopeptidase activator activity involved in apoptotic process / positive regulation of T cell receptor signaling pathway / positive regulation of mitochondrial depolarization / endonucleolytic cleavage to generate mature 3'-end of SSU-rRNA from (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / translation regulator activity / phagocytic cup / cell-cell junction assembly / 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 / negative regulation of cell-cell adhesion / entry of bacterium into host cell / iron-sulfur cluster binding / ion channel inhibitor activity / stress granule assembly / poly(U) RNA binding / GTPase activating protein binding / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / positive regulation of apoptotic signaling pathway / 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 protein S5, N-terminal / Nucleotide-binding alpha-beta plait domain superfamily / Cadherin-like superfamily / Cadherin prodomain / Ribosomal protein L2, domain 3 / Ribosomal protein L2, domain 2 / Ribosomal protein S5 domain 2-type fold, subgroup / Ribosomal protein S6, eukaryotic / Ribosomal protein S4e, central region / Ribosomal protein S4e, N-terminal ...Ribosomal protein S5, N-terminal / Nucleotide-binding alpha-beta plait domain superfamily / Cadherin-like superfamily / Cadherin prodomain / Ribosomal protein L2, domain 3 / Ribosomal protein L2, domain 2 / Ribosomal protein S5 domain 2-type fold, subgroup / Ribosomal protein S6, eukaryotic / Ribosomal protein S4e, central region / Ribosomal protein S4e, N-terminal / Ribosomal protein S9 / Ribosomal protein L25/L23 / Ribosomal protein L4/L1e, eukaryotic/archaeal, conserved site / Ribosomal protein L30, N-terminal / Ribosomal protein L23/L15e core domain superfamily / Ribosomal protein S13/S15, N-terminal / WD40/YVTN repeat-like-containing domain superfamily / Nucleic acid-binding, OB-fold / Ribosomal protein S5 / Zinc-binding ribosomal protein / Ribosomal protein L37ae/L37e / Ribosomal protein S4e / Ribosomal protein S26e / TRASH domain / Ribosomal protein S13-like, H2TH / S15/NS1, RNA-binding / K homology domain superfamily, prokaryotic type / 60S ribosomal protein L6E / Translation protein, beta-barrel domain superfamily / Ribosomal protein L24e-related / Translation protein SH3-like domain superfamily / Ribosomal protein L6 / K homology domain-like, alpha/beta / Ribosomal protein L34Ae / Ribosomal protein S15 / Ribosomal protein S17e, conserved site / Ribosomal protein S14, conserved site / Ribosomal protein S13, conserved site / Ribosomal protein S10, conserved site / Ribosomal protein L37e, conserved site / Ribosomal protein L35Ae, conserved site / Ribosomal protein L32e, conserved site / 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 S7e / Ribosomal protein S27e / Ribosomal protein L19/L19e, domain 1 / Ribosomal protein S4e, N-terminal, conserved site / Ribosomal protein L3 / Ribosomal protein S5, N-terminal, conserved site / Ribosomal protein S2, conserved site / Ribosomal S11, conserved site / Ribosomal S24e conserved site / Ubiquitin-like domain / Ribosomal protein S4, conserved site / Ribosomal protein L34e, conserved site / Ribosomal protein S8 / Ribosomal protein L30, conserved site / WD40-repeat-containing domain / Ribosomal protein L10e/L16 / Ribosomal protein L30, ferredoxin-like fold domain / Ribosomal protein L23/L25, conserved site / Ribosomal protein S8e / Ribosomal protein S12e / WD40 repeat / Ribosomal protein L7Ae conserved site / Ribosomal protein S6e / Ribosomal protein L13e / RNA-binding S4 domain / Ribosomal protein S27a / Ribosomal protein L14e domain / Ribosomal protein L38e / Ribosomal protein L37ae / Ribosomal protein L29e / Ribosomal protein L32e / Ribosomal protein L37e / Ribosomal protein L28e / Ribosomal protein S3Ae / Ribosomal protein L22e / Ribosomal protein L6, conserved site-2 / K Homology domain, type 2 / Ribosomal protein S19/S15 / Ribosomal protein L35A / Ribosomal protein L2 / Ribosomal protein L4/L1e / Ribosomal protein L5 / Cadherin-like / Ribosomal protein S24e / Ribosomal protein L40e / Ribosomal protein S11 / Ribosomal protein S21e / Ribosomal protein S10 / Ribosomal protein L7A/L8 / Ribosomal protein S4/S9, N-terminal / Ribosomal protein L29/L35 / Ribosomal protein L7Ae/L30e/S12e/Gadd45
60S ribosomal protein L30 / 40S ribosomal protein S6 / 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 S4, X isoform / 60S ribosomal protein L23a ...60S ribosomal protein L30 / 40S ribosomal protein S6 / 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 S4, X isoform / 60S ribosomal protein L23a / 40S ribosomal protein S23 / 40S ribosomal protein S14 / 60S ribosomal protein L7a / 40S ribosomal protein S11 / 40S ribosomal protein S13 / 40S ribosomal protein S29 / 40S ribosomal protein S18 / 40S ribosomal protein S30 / 60S ribosomal protein L24 / 60S ribosomal protein L39 / Receptor of activated protein C kinase 1 / 40S ribosomal protein S15a / 60S ribosomal protein L23 / 60S ribosomal protein L18 / 60S ribosomal protein L6 / 60S ribosomal protein L18a / 60S ribosomal protein L19 / 60S ribosomal protein L36a / 40S ribosomal protein S21 / 60S ribosomal protein L31 / 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 / 60S ribosomal protein L32 / 40S ribosomal protein S16 / 40S ribosomal protein S2 / 40S ribosomal protein S8 / 40S ribosomal protein S12 / 60S ribosomal protein L3 / 40S ribosomal protein S19 / 60S ribosomal protein L4 / 60S ribosomal protein L22 / 60S ribosomal protein L9 / 60S ribosomal protein L10 / 60S ribosomal protein L13 / 40S ribosomal protein S3 / 40S ribosomal protein S27 / 60S ribosomal protein L17 / 60S ribosomal protein L7 / 60S ribosomal protein L35a / Cadherin-1 / 40S ribosomal protein SA / 40S ribosomal protein S17 / 40S ribosomal protein S30 / 60S ribosomal protein L13a / 60S ribosomal protein L35 / 40S ribosomal protein S7 / 60S ribosomal protein L14 / 60S ribosomal protein L37 / 60S ribosomal protein L37a / 60S ribosomal protein L27 / 60S ribosomal protein L15 / 60S ribosomal protein L26 / 40S ribosomal protein S3a / 40S ribosomal protein S20 / 60S ribosomal protein L34 / 60S ribosomal protein L27a / 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 L5 / 60S ribosomal protein L36
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3 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: 6ole

SummaryFull reportAbout validation report
History
DepositionFeb 21, 2019-
Header (metadata) releaseMar 20, 2019-
Map releaseMar 20, 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: 0.02
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.02
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  • Surface view with fitted model
  • Atomic models: PDB-6ole
  • Surface level: 0.02
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Structure viewerEM map:
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Supplemental images

Downloads & links

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Map

FileDownload / File: emd_0600.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 EMDB: 0.02 / Movie #1: 0.02
Minimum - Maximum-0.06671343 - 0.14892814
Average (Standard dev.)0.00041651924 (±0.0066053597)
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-0.0670.1490.000

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Supplemental data

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Additional map: PF846 stalled human ribosome nascent chain complex (CDH1-RNC)...

Fileemd_0600_additional.map
AnnotationPF846 stalled human ribosome nascent chain complex (CDH1-RNC) in rotated state with AP tRNA and PE tRNA. Map is not sharpened.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: Half map of PF846 stalled human ribosome nascent...

Fileemd_0600_half_map_1.map
AnnotationHalf map of PF846 stalled human ribosome nascent chain complex (CDH1-RNC) in rotated state with AP tRNA and PE tRNA.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: Half map of PF846 stalled human ribosome nascent...

Fileemd_0600_half_map_2.map
AnnotationHalf map of PF846 stalled human ribosome nascent chain complex (CDH1-RNC) in rotated state with AP tRNA and PE tRNA.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Sample components

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Entire Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug...

EntireName: Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug-like molecule with AP tRNA and PE tRNA
Number of components: 1

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Component #1: protein, Human ribosome nascent chain complex (CDH1-RNC) stalled ...

ProteinName: Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug-like molecule with AP tRNA and PE tRNA
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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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionpH: 7.8
Support filmunspecified
VitrificationCryogen name: ETHANE / Temperature: 277 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: 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: 731100
3D reconstructionResolution: 3 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: 71
Output model

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