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- EMDB-0598: Structure of a drug-like molecule stalled ribosome nascent chain ... -

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Entry
Database: EMDB / ID: EMD-0598
TitleStructure of a drug-like molecule stalled ribosome nascent chain complex (PCSK9_RNC) in non-rotated state with PP tRNA
Map data
SampleDrug-like molecule stalled human ribosome nascent chain complex (PCSK9-RNC) in non-rotated state with PP tRNA:
nucleic-acidNucleic acid
Function / homology
Function and homology information


Regulation of TNFR1 signaling / Degradation of GLI2 by the proteasome / Degradation of GLI1 by the proteasome / CLEC7A (Dectin-1) signaling / Dectin-1 mediated noncanonical NF-kB signaling / Hh mutants that don't undergo autocatalytic processing are degraded by ERAD / Hedgehog ligand biogenesis / TNFR1-induced NFkappaB signaling pathway / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / TNFR1-mediated ceramide production ...Regulation of TNFR1 signaling / Degradation of GLI2 by the proteasome / Degradation of GLI1 by the proteasome / CLEC7A (Dectin-1) signaling / Dectin-1 mediated noncanonical NF-kB signaling / Hh mutants that don't undergo autocatalytic processing are degraded by ERAD / Hedgehog ligand biogenesis / TNFR1-induced NFkappaB signaling pathway / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / TNFR1-mediated ceramide production / Pink/Parkin Mediated Mitophagy / Regulation of FZD by ubiquitination / Degradation of DVL / Degradation of AXIN / Asymmetric localization of PCP proteins / AUF1 (hnRNP D0) binds and destabilizes mRNA / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / GLI3 is processed to GLI3R by the proteasome / Hedgehog 'on' state / TAK1 activates NFkB by phosphorylation and activation of IKKs complex / TNFR2 non-canonical NF-kB pathway / MAPK6/MAPK4 signaling / HDR through Homologous Recombination (HRR) / MAP3K8 (TPL2)-dependent MAPK1/3 activation / Defective CFTR causes cystic fibrosis / NIK-->noncanonical NF-kB signaling / Regulation of necroptotic cell death / Negative regulation of MAPK pathway / RHO GTPases Activate Formins / Negative regulation of FGFR1 signaling / Regulation of RAS by GAPs / Termination of translesion DNA synthesis / Translesion synthesis by POLI / Translesion synthesis by POLK / Negative regulation of FGFR4 signaling / Negative regulation of FGFR3 signaling / Negative regulation of FGFR2 signaling / activated TAK1 mediates p38 MAPK activation / Circadian Clock / Josephin domain DUBs / p75NTR recruits signalling complexes / Downregulation of SMAD2/3:SMAD4 transcriptional activity / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / Downregulation of TGF-beta receptor signaling / Activated NOTCH1 Transmits Signal to the Nucleus / NOTCH1 Intracellular Domain Regulates Transcription / Regulation of activated PAK-2p34 by proteasome mediated degradation / NF-kB is activated and signals survival / NRIF signals cell death from the nucleus / Selenocysteine synthesis / Downstream TCR signaling / TCF dependent signaling in response to WNT / Degradation of beta-catenin by the destruction complex / Viral mRNA Translation / SCF(Skp2)-mediated degradation of p27/p21 / EGFR downregulation / Vif-mediated degradation of APOBEC3G / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Separation of Sister Chromatids / ABC-family proteins mediated transport / NOTCH2 Activation and Transmission of Signal to the Nucleus / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / Myoclonic epilepsy of Lafora / Deactivation of the beta-catenin transactivating complex / Autodegradation of the E3 ubiquitin ligase COP1 / Glycogen synthesis / RMTs methylate histone arginines / Regulation of innate immune responses to cytosolic DNA / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / Resolution of Sister Chromatid Cohesion / FCERI mediated NF-kB activation / Constitutive Signaling by NOTCH1 HD Domain Mutants / Stimuli-sensing channels / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Regulation of PLK1 Activity at G2/M Transition / Oncogene Induced Senescence / Senescence-Associated Secretory Phenotype (SASP) / Oxidative Stress Induced Senescence / UCH proteinases / Ub-specific processing proteases / SRP-dependent cotranslational protein targeting to membrane / Regulation of PTEN stability and activity / TICAM1-dependent activation of IRF3/IRF7 / NOTCH3 Activation and Transmission of Signal to the Nucleus / Regulation of expression of SLITs and ROBOs / ER Quality Control Compartment (ERQC) / LDL clearance / Post-translational protein phosphorylation / Neddylation / Regulation of PTEN localization / Interleukin-1 signaling / Regulation of RUNX3 expression and activity / Regulation of RUNX2 expression and activity / RUNX1 regulates transcription of genes involved in differentiation of HSCs / Protein methylation / InlA-mediated entry of Listeria monocytogenes into host cells / InlB-mediated entry of Listeria monocytogenes into host cell / E3 ubiquitin ligases ubiquitinate target proteins / TICAM1,TRAF6-dependent induction of TAK1 complex / Peroxisomal protein import
Ribosomal protein L31e, conserved site / Ribosomal protein S19/S15 / Ribosomal protein S11 / Ribosomal protein L40e / Ribosomal protein S24e / Ribosomal protein L5 / Ribosomal protein L4/L1e / Ribosomal protein L2 / Ribosomal protein L6, conserved site-2 / Ribosomal protein L7A/L8 ...Ribosomal protein L31e, conserved site / Ribosomal protein S19/S15 / Ribosomal protein S11 / Ribosomal protein L40e / Ribosomal protein S24e / Ribosomal protein L5 / Ribosomal protein L4/L1e / Ribosomal protein L2 / Ribosomal protein L6, conserved site-2 / Ribosomal protein L7A/L8 / Ribosomal protein L22e / Ribosomal protein L28e / Ribosomal protein L29e / Ribosomal protein L37ae / Ribosomal protein L38e / Ribosomal protein L14e domain / Ribosomal protein S27a / Ribosomal protein S21e / Ribosomal protein S4/S9, N-terminal / Ribosomal protein L7Ae conserved site / Ribosomal protein L13e / Ribosomal protein L15, conserved site / Ribosomal protein L10e / Ribosomal protein S14 / Ribosomal protein S17e / Ribosomal protein S19e / Ribosomal protein S3, C-terminal / Ribosomal protein S6e / Ribosomal protein L32e / Ribosomal protein S13 / Ribosomal protein L37e / Ribosomal protein S3Ae / WD40 repeat / Ribosomal protein L35A / Ribosomal protein S10 / Ribosomal protein L29/L35 / Ribosomal protein S2 / RNA-binding S4 domain / Ribosomal protein L7Ae/L30e/S12e/Gadd45 / Ribosomal protein L27e / K homology domain superfamily, prokaryotic type / 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 / S15/NS1, RNA-binding / KOW / Peptidase S8 propeptide/proteinase inhibitor I9 / Ribosomal protein S13-like, H2TH / TRASH domain / Ribosomal protein L37ae/L37e / Zinc-binding ribosomal protein / Nucleic acid-binding, OB-fold / Ribosomal protein S13/S15, N-terminal / Ribosomal protein L24/L26, conserved site / Ribosomal protein L13 / K Homology domain, type 2 / Ribosomal protein S3, eukaryotic/archaeal / Ribosomal protein S25 / Ribosomal protein S5, C-terminal / Plectin/S10, N-terminal / Ribosomal protein L5 eukaryotic/L18 archaeal / Ribosomal protein L6, N-terminal / Ribosomal protein L23/L25, N-terminal / Ribosomal protein S23, eukaryotic/archaeal / Ribosomal protein S2, eukaryotic/archaeal / Ribosomal protein L26/L24, eukaryotic/archaeal / 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 L21e / Ribosomal protein L22/L17 / Ribosomal protein L23/L15e core domain superfamily / Ribosomal protein S10p/S20e / Ribosomal protein S11 / Ribosomal protein S8 / WD domain, G-beta repeat / Ribosomal protein S9/S16 / Ribosomal protein S17 / Ribosomal protein L6 / Ribosomal protein S5, N-terminal domain / KOW motif / Ribosomal protein L30p/L7e / Ribosomal protein S2 / Ribosomal protein S15 / Ribosomal protein L3 / Ribosomal protein L5 / Ribosomal protein L23 / Ribosomal protein S14p/S29e / Ribosomal protein S13/S18 / Ribosomal protein L13 / Ubiquitin family / Ribosomal S3Ae family
40S ribosomal protein S6 / 60S ribosomal protein L30 / 40S ribosomal protein S28 / 40S ribosomal protein S26 / 40S ribosomal protein S25 / 40S ribosomal protein S24 / 40S ribosomal protein S15 / 40S ribosomal protein S8 / 60S ribosomal protein L23a / 60S ribosomal protein L39 ...40S ribosomal protein S6 / 60S ribosomal protein L30 / 40S ribosomal protein S28 / 40S ribosomal protein S26 / 40S ribosomal protein S25 / 40S ribosomal protein S24 / 40S ribosomal protein S15 / 40S ribosomal protein S8 / 60S ribosomal protein L23a / 60S ribosomal protein L39 / 40S ribosomal protein S11 / 40S ribosomal protein S13 / 40S ribosomal protein S29 / 40S ribosomal protein S18 / 40S ribosomal protein S23 / 40S ribosomal protein S14 / 40S ribosomal protein S16 / 60S ribosomal protein L7a / 60S ribosomal protein L32 / 60S ribosomal protein L31 / 60S ribosomal protein L36a / Similar to ribosomal protein L23 / Proprotein convertase subtilisin/kexin type 9 / 60S ribosomal protein L18 / 60S ribosomal protein L6 / 60S ribosomal protein L18a / 60S ribosomal protein L19 / 60S ribosomal protein L24 / 60S ribosomal protein L11 / Receptor of activated protein C kinase 1 / 40S ribosomal protein S21 / 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 S15a / 60S ribosomal protein L4 / 40S ribosomal protein S7 / 40S ribosomal protein S3 / 40S ribosomal protein S19 / 60S ribosomal protein L22 / 60S ribosomal protein L9 / 60S ribosomal protein L10 / 60S ribosomal protein L13 / 40S ribosomal protein S12 / 40S ribosomal protein S4, Y isoform 1 / 60S ribosomal protein L13a / 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 / 60S ribosomal protein L3 / 40S ribosomal protein S27 / 60S ribosomal protein L37 / 60S ribosomal protein L34 / 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 L14 / 60S ribosomal protein L29 / 60S ribosomal protein L35 / 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 L27a / 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: 6olz

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: 0.024
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.024
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: : PDB-6olz
  • Surface level: 0.024
  • 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_0598.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.)
1.22 Å/pix.
x 400 pix.
= 488. Å
1.22 Å/pix.
x 400 pix.
= 488. Å
1.22 Å/pix.
x 400 pix.
= 488. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.22 Å
Density
Contour LevelBy AUTHOR: 0.022 / Movie #1: 0.024
Minimum - Maximum-0.057956874 - 0.10376459
Average (Standard dev.)0.000268779 (±0.007156887)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 488.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.221.221.22
M x/y/z400400400
origin x/y/z0.0000.0000.000
length x/y/z488.000488.000488.000
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS400400400
D min/max/mean-0.0580.1040.000

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Supplemental data

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Sample components

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Entire Drug-like molecule stalled human ribosome nascent chain complex (...

EntireName: Drug-like molecule stalled human ribosome nascent chain complex (PCSK9-RNC) in non-rotated state with PP tRNA
Number of components: 2

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

ProteinName: Drug-like molecule stalled human ribosome nascent chain complex (PCSK9-RNC) in non-rotated state with PP 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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Component #2: nucleic-acid, human ribosome with nascent chain

nucleic acidName: human ribosome with nascent chain / Class: RNA
Details: Nascent chain sequence including CDH1 domain V and PCSK9 1-35
Structure: OTHER / Synthetic: No
Sequence:
SDVNDNAPIP EPRTIFFCER NPKPQVINII DADLPPNTSP FTAELTHGAS ANWTIQYNDP TQESIILKPK MALEVGDYKI NLKLMDNQNK DQVTTLEVSV CDCEGAAGVC RKAQPVEAGL QIPAILGILG MGTVSSRRSW WPLPLLLLLL LLLGPAGARA QEDED
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: 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: 7214
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: 80
Output model

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