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- EMDB-0599: Structure of a drug-like molecule stalled CDH1 ribosome nascent c... -

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Entry
Database: EMDB / ID: EMD-0599
TitleStructure of a drug-like molecule stalled CDH1 ribosome nascent chain complex (CDH1-RNC) in rotated state with AA tRNA and PE tRNA
Map data
Samplehuman ribosome nascent chain complex (CDH1-RNC) stalled by a drug-like molecule with AA tRNA and PE tRNA
Function / homology
Function and homology information


SCF(Skp2)-mediated degradation of p27/p21 / Gap-filling DNA repair synthesis and ligation in TC-NER / APC-Cdc20 mediated degradation of Nek2A / SRP-dependent cotranslational protein targeting to membrane / Vpu mediated degradation of CD4 / Vif-mediated degradation of APOBEC3G / EGFR downregulation / Major pathway of rRNA processing in the nucleolus and cytosol / rRNA modification in the nucleus and cytosol / Viral mRNA Translation ...SCF(Skp2)-mediated degradation of p27/p21 / Gap-filling DNA repair synthesis and ligation in TC-NER / APC-Cdc20 mediated degradation of Nek2A / SRP-dependent cotranslational protein targeting to membrane / Vpu mediated degradation of CD4 / Vif-mediated degradation of APOBEC3G / EGFR downregulation / Major pathway of rRNA processing in the nucleolus and cytosol / rRNA modification in the nucleus and cytosol / Viral mRNA Translation / Degradation of beta-catenin by the destruction complex / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / TCF dependent signaling in response to WNT / Downstream TCR signaling / Fanconi Anemia Pathway / NRIF signals cell death from the nucleus / p75NTR recruits signalling complexes / Regulation of TP53 Activity through Phosphorylation / NF-kB is activated and signals survival / Dual incision in TC-NER / Regulation of activated PAK-2p34 by proteasome mediated degradation / NOTCH1 Intracellular Domain Regulates Transcription / Activated NOTCH1 Transmits Signal to the Nucleus / Integrin cell surface interactions / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Downregulation of TGF-beta receptor signaling / Formation of TC-NER Pre-Incision Complex / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / Dual Incision in GG-NER / Gap-filling DNA repair synthesis and ligation in GG-NER / Downregulation of SMAD2/3:SMAD4 transcriptional activity / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Assembly Of The HIV Virion / Membrane binding and targetting of GAG proteins / Separation of Sister Chromatids / L13a-mediated translational silencing of Ceruloplasmin expression / ISG15 antiviral mechanism / Stabilization of p53 / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / G2/M Checkpoints / ER-Phagosome pathway / Cyclin D associated events in G1 / CDK-mediated phosphorylation and removal of Cdc6 / Downregulation of ERBB4 signaling / Spry regulation of FGF signaling / Orc1 removal from chromatin / Downregulation of ERBB2:ERBB3 signaling / Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal / Degradation of the extracellular matrix / Peptide chain elongation / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / DDX58/IFIH1-mediated induction of interferon-alpha/beta / APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 / APC/C:Cdc20 mediated degradation of Securin / SCF-beta-TrCP mediated degradation of Emi1 / Autodegradation of Cdh1 by Cdh1:APC/C / Regulation of TP53 Degradation / APC/C:Cdc20 mediated degradation of Cyclin B / Regulation of TP53 Activity through Methylation / Budding and maturation of HIV virion / TICAM1, RIP1-mediated IKK complex recruitment / Negative regulation of MET activity / CDT1 association with the CDC6:ORC:origin complex / NOD1/2 Signaling Pathway / mTORC1-mediated signalling / Mitotic Prometaphase / Selenocysteine synthesis / Resolution of Sister Chromatid Cohesion / MAP3K8 (TPL2)-dependent MAPK1/3 activation / Hedgehog 'on' state / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / Josephin domain DUBs / Regulation of TNFR1 signaling / TNFR1-induced NFkappaB signaling pathway / Hedgehog ligand biogenesis / Hh mutants that don't undergo autocatalytic processing are degraded by ERAD / Dectin-1 mediated noncanonical NF-kB signaling / CLEC7A (Dectin-1) signaling / UCH proteinases / Degradation of GLI1 by the proteasome / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / RHO GTPases activate IQGAPs / TNFR1-mediated ceramide production / Negative regulation of FGFR1 signaling / Regulation of FZD by ubiquitination / Negative regulation of FGFR2 signaling / Negative regulation of FGFR3 signaling / Negative regulation of FGFR4 signaling / Translesion synthesis by POLK / Translesion synthesis by POLI / Termination of translesion DNA synthesis / Regulation of RAS by GAPs / RHO GTPases Activate Formins / TNFR2 non-canonical NF-kB pathway / Negative regulation of MAPK pathway / Regulation of necroptotic cell death / NIK-->noncanonical NF-kB signaling / MAPK6/MAPK4 signaling
Ribosomal protein L31e, conserved site / Ribosomal protein L4/L1e, eukaryotic/archaeal, conserved site / Ribosomal protein L37ae/L37e / Zinc-binding ribosomal protein / Nucleic acid-binding, OB-fold / Ribosomal protein S13/S15, N-terminal / Nucleotide-binding alpha-beta plait domain superfamily / Ribosomal protein L23/L15e core domain superfamily / Ribosomal protein L30, N-terminal / Ribosomal protein L25/L23 ...Ribosomal protein L31e, conserved site / Ribosomal protein L4/L1e, eukaryotic/archaeal, conserved site / Ribosomal protein L37ae/L37e / Zinc-binding ribosomal protein / Nucleic acid-binding, OB-fold / Ribosomal protein S13/S15, N-terminal / Nucleotide-binding alpha-beta plait domain superfamily / Ribosomal protein L23/L15e core domain superfamily / Ribosomal protein L30, N-terminal / Ribosomal protein L25/L23 / Ribosomal protein S13-like, H2TH / Ribosomal protein S5, N-terminal / Ribosomal protein S4e, N-terminal / Ribosomal protein S4e, central region / Ribosomal protein S6, eukaryotic / Ribosomal protein S5 domain 2-type fold, subgroup / Ribosomal protein L2, domain 2 / Ribosomal protein L2, domain 3 / Cadherin prodomain / TRASH domain / S15/NS1, RNA-binding / WD40/YVTN repeat-like-containing domain superfamily / Ribosomal protein L13 / 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 / Ribosomal protein L13, eukaryotic/archaeal / Ribosomal protein L26/L24, eukaryotic/archaeal / KOW / K homology domain superfamily, prokaryotic type / Ribosomal protein L24/L26, conserved site / Ribosomal protein L7, eukaryotic / Ribosomal protein S12/S23 / Ribosomal protein S30 / Ribosomal protein L41 / Ribosomal protein L34Ae / Translation protein SH3-like domain superfamily / Translation protein, beta-barrel domain superfamily / Cadherin-like superfamily / K homology domain-like, alpha/beta / Ribosomal protein S3, eukaryotic/archaeal / Ribosomal protein L7Ae/L8/Nhp2 family / Ribosomal protein S14, conserved site / Ribosomal protein S17e, conserved site / Ribosomal protein S19e, conserved site / Ribosomal protein S21e, conserved site / Ribosomal protein S3, conserved site / Ribosomal protein S3Ae, conserved site / Ribosomal protein S6e, conserved site / Ribosomal protein S8e, conserved site / WD40 repeat, conserved site / Ribosomal protein S10, conserved site / Ribosomal protein L3, conserved site / Ubiquitin conserved site / Ubiquitin / Ribosomal protein L14P, conserved site / Ribosomal protein S17, conserved site / Ribosomal protein L23 / Ribosomal protein L6, alpha-beta domain / Ribosomal protein S5, C-terminal domain / Ribosomal protein S13, conserved site / Ribosomal protein L37e, conserved site / Ribosomal protein L19/L19e, domain 1 / Ribosomal protein S2, conserved site / Ribosomal protein L30, ferredoxin-like fold domain / Ribosomal protein L10e/L16 / WD40-repeat-containing domain / Ribosomal protein L30, conserved site / Ribosomal protein L34e, conserved site / Ribosomal protein S4, conserved site / Ribosomal S24e conserved site / Ribosomal S11, conserved site / Ribosomal protein S5, N-terminal, conserved site / Ribosomal protein L35Ae, conserved site / Ribosomal protein S4e, N-terminal, conserved site / Ribosomal protein L29, conserved site / 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 S2, eukaryotic/archaeal / Ribosomal protein S23, eukaryotic/archaeal / G-protein beta WD-40 repeat / Ribosomal protein S4e / Ribosomal protein S27e / Ribosomal protein L3 / Ubiquitin domain / Ribosomal protein S8 / Ribosomal protein L6 / Ribosomal protein S9 / Ribosomal protein S5 / Ribosomal protein S26e / Ribosomal protein S7e / 60S ribosomal protein L6E / Ribosomal protein L24e-related
40S ribosomal protein S4, X isoform / 40S ribosomal protein S26 / 40S ribosomal protein S25 / 40S ribosomal protein S24 / 40S ribosomal protein S15 / 40S ribosomal protein S6 / 60S ribosomal protein L23a / 40S ribosomal protein S18 / 60S ribosomal protein L7a / 40S ribosomal protein S11 ...40S ribosomal protein S4, X isoform / 40S ribosomal protein S26 / 40S ribosomal protein S25 / 40S ribosomal protein S24 / 40S ribosomal protein S15 / 40S ribosomal protein S6 / 60S ribosomal protein L23a / 40S ribosomal protein S18 / 60S ribosomal protein L7a / 40S ribosomal protein S11 / 40S ribosomal protein S13 / 40S ribosomal protein S29 / 60S ribosomal protein L30 / 40S ribosomal protein S23 / 40S ribosomal protein S14 / 40S ribosomal protein S16 / 40S ribosomal protein S28 / 60S ribosomal protein L11 / 60S ribosomal protein L39 / Receptor of activated protein C kinase 1 / Similar to ribosomal protein L23 / 60S ribosomal protein L18 / 60S ribosomal protein L6 / 60S ribosomal protein L18a / 60S ribosomal protein L19 / 60S ribosomal protein L36a / 60S ribosomal protein L24 / 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 / 40S ribosomal protein S8 / 60S ribosomal protein L32 / 40S ribosomal protein S15a / 60S ribosomal protein L27 / 40S ribosomal protein S7 / 40S ribosomal protein S3 / 60S ribosomal protein L4 / 60S ribosomal protein L22 / 60S ribosomal protein L9 / 60S ribosomal protein L10 / 60S ribosomal protein L13 / 40S ribosomal protein S12 / 60S ribosomal protein L17 / 60S ribosomal protein L3 / 60S ribosomal protein L7 / 60S ribosomal protein L35a / 40S ribosomal protein S2 / Cadherin-1 / 40S ribosomal protein SA / 40S ribosomal protein S17 / 40S ribosomal protein S30 / 40S ribosomal protein S19 / 60S ribosomal protein L13a / 60S ribosomal protein L37 / 60S ribosomal protein L29 / 60S ribosomal protein L37a / 60S ribosomal protein L15 / 60S ribosomal protein L26 / 40S ribosomal protein S3a / 40S ribosomal protein S20 / 60S ribosomal protein L14 / 60S ribosomal protein L34 / 40S ribosomal protein S10 / 40S ribosomal protein S27 / 40S ribosomal protein S5 / 40S ribosomal protein S9 / 60S ribosomal protein L28 / 60S ribosomal protein L21 / 60S ribosomal protein L5 / 60S ribosomal protein L27a / 60S ribosomal protein L35 / 60S ribosomal protein L36
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsLi W / Cate JHD
Funding support3 items
OrganizationGrant numberCountry
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: 6olf

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
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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-6olf
  • 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_0599.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: 0.02 / Movie #1: 0.02
Minimum - Maximum-0.04674063 - 0.09558096
Average (Standard dev.)0.00046730065 (±0.005918665)
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-0.0470.0960.000

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Supplemental data

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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 AA 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 AA 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: 10350
3D reconstructionResolution: 3.9 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: 73
Output model

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