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

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Basic information

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 dataPF846 stalled human ribosome nascent chain complex (CDH1-RNC) in rotated state with AP tRNA and PE tRNA. Map is sharpened.
Sample
  • Complex: Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug-like molecule with AP tRNA and PE tRNA
Function / homology
Function and homology information


response to Gram-positive bacterium / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / pituitary gland development / gamma-catenin binding / negative regulation of axon extension / cell-cell adhesion mediated by cadherin / cellular response to indole-3-methanol / flotillin complex / positive regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis / negative regulation of endoplasmic reticulum unfolded protein response ...response to Gram-positive bacterium / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / pituitary gland development / gamma-catenin binding / negative regulation of axon extension / cell-cell adhesion mediated by cadherin / cellular response to indole-3-methanol / flotillin complex / positive regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis / negative regulation of endoplasmic reticulum unfolded protein response / embryonic brain development / eukaryotic 80S initiation complex / oxidized pyrimidine DNA binding / response to TNF agonist / positive regulation of base-excision repair / negative regulation of protein neddylation / Formation of definitive endoderm / calcium-dependent cell-cell adhesion via plasma membrane cell adhesion molecules / protein tyrosine kinase inhibitor activity / translation at presynapse / positive regulation of respiratory burst involved in inflammatory response / axial mesoderm development / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage / positive regulation of gastrulation / negative regulation of formation of translation preinitiation complex / nucleolus organization / ribosomal protein import into nucleus / IRE1-RACK1-PP2A complex / : / positive regulation of endodeoxyribonuclease activity / positive regulation of Golgi to plasma membrane protein transport / 90S preribosome assembly / TNFR1-mediated ceramide production / negative regulation of RNA splicing / negative regulation of DNA repair / TORC2 complex binding / Adherens junctions interactions / laminin receptor activity / catenin complex / Apoptotic cleavage of cell adhesion proteins / GAIT complex / negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide / oxidized purine DNA binding / supercoiled DNA binding / neural crest cell differentiation / middle ear morphogenesis / NF-kappaB complex / GTPase activating protein binding / ubiquitin-like protein conjugating enzyme binding / regulation of establishment of cell polarity / negative regulation of phagocytosis / cell-cell junction assembly / positive regulation of ubiquitin-protein transferase activity / Formation of the ternary complex, and subsequently, the 43S complex / rRNA modification in the nucleus and cytosol / adherens junction organization / cytoplasmic side of rough endoplasmic reticulum membrane / erythrocyte homeostasis / A band / regulation of G1 to G0 transition / alpha-beta T cell differentiation / exit from mitosis / pigmentation / 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 kinase A binding / protein-DNA complex disassembly / positive regulation of DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / apical junction complex / Ribosomal scanning and start codon recognition / negative regulation of ubiquitin protein ligase activity / optic nerve development / ankyrin binding / ion channel inhibitor activity / Translation initiation complex formation / mammalian oogenesis stage / positive regulation of mitochondrial depolarization / response to aldosterone / retinal ganglion cell axon guidance / G1 to G0 transition / homeostatic process / activation-induced cell death of T cells / negative regulation of cell-cell adhesion / lung morphogenesis / cellular response to lithium ion / negative regulation of Wnt signaling pathway / fibroblast growth factor binding / positive regulation of T cell receptor signaling pathway / positive regulation of activated T cell proliferation / regulation of cell division / Protein hydroxylation / iron-sulfur cluster binding / BH3 domain binding / mTORC1-mediated signalling / macrophage chemotaxis / SARS-CoV-1 modulates host translation machinery / homophilic cell adhesion via plasma membrane adhesion molecules / Peptide chain elongation / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator
Similarity search - Function
Cadherin prodomain like / Cadherin prodomain / Cadherin prodomain like / Cadherin, Y-type LIR-motif / Cadherin, Y-type LIR-motif / Catenin binding domain superfamily / Cadherin / 40S ribosomal protein SA / Cadherin conserved site / Cadherin domain signature. ...Cadherin prodomain like / Cadherin prodomain / Cadherin prodomain like / Cadherin, Y-type LIR-motif / Cadherin, Y-type LIR-motif / Catenin binding domain superfamily / Cadherin / 40S ribosomal protein SA / Cadherin conserved site / Cadherin domain signature. / 40S ribosomal protein SA, C-terminal domain / Cadherin repeats. / 40S ribosomal protein SA C-terminus / Cadherin domain / Cadherins domain profile. / Cadherin-like / Cadherin-like superfamily / Ubiquitin-like protein FUBI / Ribosomal protein L6, N-terminal / Ribosomal protein L6, N-terminal domain / Ribosomal protein L30e / Ribosomal protein L2, archaeal-type / Ribosomal protein L28e / Ribosomal protein L41 / Ribosomal L15/L27a, N-terminal / Ribosomal protein L41 / : / Ribosomal protein L23 / Ribosomal L28e/Mak16 / Ribosomal L28e protein family / Ribosomal protein S21e, conserved site / Ribosomal protein S26e / Ribosomal protein S26e superfamily / Ribosomal protein S26e / Ribosomal protein S26e signature. / Ribosomal protein S21e / Ribosomal protein S21e superfamily / Ribosomal protein S21e / Ribosomal protein S2, eukaryotic / : / Ribosomal protein S21e signature. / Ribosomal protein S12e signature. / metallochaperone-like domain / Ribosomal protein S12e / Ribosomal protein S5, eukaryotic/archaeal / TRASH domain / Ribosomal protein L29e / Ribosomal protein S2, eukaryotic/archaeal / Ribosomal L29e protein family / Ribosomal protein S19e, conserved site / Ribosomal protein S19e signature. / Small (40S) ribosomal subunit Asc1/RACK1 / 40S Ribosomal protein S10 / S27a-like superfamily / Ribosomal protein S10, eukaryotic/archaeal / Ribosomal protein L13e, conserved site / Ribosomal protein L13e signature. / Ribosomal protein L22e / Plectin/S10, N-terminal / Ribosomal protein L22e superfamily / Ribosomal L22e protein family / Plectin/S10 domain / Ribosomal protein L38e / Ribosomal protein L38e superfamily / Ribosomal L38e protein family / Ribosomal protein S25 / S25 ribosomal protein / : / Ribosomal protein L13e / Ribosomal protein L13e / Ribosomal protein S17e, conserved site / Ribosomal protein S17e signature. / Ribosomal protein S27a / Ribosomal protein S27a / Ribosomal protein S27a / Ribosomal protein S8e subdomain, eukaryotes / Ribosomal protein L14e domain / Ribosomal protein S30 / Ribosomal protein S30 / 40S ribosomal protein S29/30S ribosomal protein S14 type Z / Ribosomal protein L27e, conserved site / Ribosomal protein L27e signature. / Ribosomal protein L44e signature. / Ribosomal protein S7e signature. / Ribosomal protein L10e, conserved site / Ribosomal protein L10e signature. / Ribosomal protein L32e, conserved site / Ribosomal protein S3, eukaryotic/archaeal / Ribosomal protein L10e / Ribosomal protein L19, eukaryotic / Ribosomal protein L14 / Ribosomal protein S19e / Ribosomal protein S3Ae, conserved site / Ribosomal protein S19e / Ribosomal protein S3Ae signature. / Ribosomal_S19e / Ribosomal protein L14, KOW motif / 60S ribosomal protein L18a/ L20, eukaryotes / Ribosomal protein S27e signature. / Ribosomal protein S4e, N-terminal, conserved site
Similarity search - Domain/homology
FAU ubiquitin like and ribosomal protein S30 fusion / Small ribosomal subunit protein eS17 / Small ribosomal subunit protein uS2 / Cadherin-1 / 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 ...FAU ubiquitin like and ribosomal protein S30 fusion / Small ribosomal subunit protein eS17 / Small ribosomal subunit protein uS2 / Cadherin-1 / 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: 3.0 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 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
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6ole
  • Surface level: 0.02
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_0600.png

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)
AnnotationPF846 stalled human ribosome nascent chain complex (CDH1-RNC) in rotated state with AP tRNA and PE tRNA. Map is sharpened.
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

Histogram

Histogram (log scale)

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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

Histogram

Histogram (log scale)

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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

Histogram

Histogram (log scale)

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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
Components
  • Complex: Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug-like molecule with AP tRNA and PE tRNA

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Supramolecule #1: Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug...

SupramoleculeName: Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug-like molecule with AP tRNA and PE tRNA
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HeLa
Molecular weightTheoretical: 4.3 MDa

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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
GridDetails: unspecified
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 731100
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Overall B value: 71
Output model

PDB-6ole:
Human ribosome nascent chain complex (CDH1-RNC) stalled by a drug-like molecule with AP and PE tRNAs

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