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- EMDB-0597: Structure of a drug-like molecule stalled ribosome nascent chain ... -

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Entry
Database: EMDB / ID: EMD-0597
TitleStructure of a drug-like molecule stalled ribosome nascent chain complex (PCSK9-RNC) in rotated state with AA tRAN and PE tRNA
Map data
SampleDrug-like molecule PF846 stalled human ribosome nascent chain complex, PCSK9-RNC in rotated state with AA tRNA and PE tRNA
Function / homology
Function and homology information


CLEC7A (Dectin-1) signaling / Negative regulation of FGFR1 signaling / Hedgehog 'on' state / TNFR1-mediated ceramide production / GLI3 is processed to GLI3R by the proteasome / Degradation of GLI2 by the proteasome / Degradation of GLI1 by the proteasome / Dectin-1 mediated noncanonical NF-kB signaling / Negative regulation of FGFR3 signaling / Hh mutants that don't undergo autocatalytic processing are degraded by ERAD ...CLEC7A (Dectin-1) signaling / Negative regulation of FGFR1 signaling / Hedgehog 'on' state / TNFR1-mediated ceramide production / GLI3 is processed to GLI3R by the proteasome / Degradation of GLI2 by the proteasome / Degradation of GLI1 by the proteasome / Dectin-1 mediated noncanonical NF-kB signaling / Negative regulation of FGFR3 signaling / Hh mutants that don't undergo autocatalytic processing are degraded by ERAD / Hedgehog ligand biogenesis / TNFR1-induced NFkappaB signaling pathway / Regulation of TNFR1 signaling / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / Pink/Parkin Mediated Mitophagy / Regulation of FZD by ubiquitination / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / Degradation of AXIN / Defective CFTR causes cystic fibrosis / Ub-specific processing proteases / Josephin domain DUBs / UCH proteinases / MAPK6/MAPK4 signaling / HDR through Homologous Recombination (HRR) / MAP3K8 (TPL2)-dependent MAPK1/3 activation / NIK-->noncanonical NF-kB signaling / Translesion synthesis by POLK / Regulation of necroptotic cell death / Negative regulation of MAPK pathway / TNFR2 non-canonical NF-kB pathway / RHO GTPases Activate Formins / Regulation of RAS by GAPs / Termination of translesion DNA synthesis / Translesion synthesis by POLI / Degradation of DVL / Asymmetric localization of PCP proteins / Metalloprotease DUBs / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Senescence-Associated Secretory Phenotype (SASP) / Oxidative Stress Induced Senescence / Resolution of Sister Chromatid Cohesion / Separation of Sister Chromatids / Selenocysteine synthesis / Downregulation of SMAD2/3:SMAD4 transcriptional activity / Regulation of PLK1 Activity at G2/M Transition / 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 / p75NTR recruits signalling complexes / Oncogene Induced Senescence / Constitutive Signaling by NOTCH1 PEST Domain Mutants / AUF1 (hnRNP D0) binds and destabilizes mRNA / Deactivation of the beta-catenin transactivating complex / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / activated TAK1 mediates p38 MAPK activation / TAK1 activates NFkB by phosphorylation and activation of IKKs complex / Circadian Clock / ABC-family proteins mediated transport / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / Myoclonic epilepsy of Lafora / Autodegradation of the E3 ubiquitin ligase COP1 / Stimuli-sensing channels / Glycogen synthesis / RMTs methylate histone arginines / Regulation of innate immune responses to cytosolic DNA / NOTCH2 Activation and Transmission of Signal to the Nucleus / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / FCERI mediated NF-kB activation / Constitutive Signaling by NOTCH1 HD Domain Mutants / Ovarian tumor domain proteases / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / Downstream TCR signaling / Neddylation / 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 / Regulation of PTEN stability and activity / Interleukin-1 signaling / Regulation of PTEN localization / 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 / TICAM1,TRAF6-dependent induction of TAK1 complex / Peroxisomal protein import / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / Negative regulation of NOTCH4 signaling / Antigen processing: Ubiquitination & Proteasome degradation / Amyloid fiber formation / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)
Ribosomal protein L6, alpha-beta domain / Ribosomal protein S10, 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 L35Ae, conserved site ...Ribosomal protein L6, alpha-beta domain / Ribosomal protein S10, 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 L35Ae, conserved site / Ribosomal protein L37e, conserved site / Ribosomal protein S13, conserved site / Ribosomal protein S5, N-terminal, conserved site / 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 / Ribosomal protein L7Ae/L8/Nhp2 family / Ribosomal protein S4e, N-terminal, conserved site / Ribosomal protein S2, conserved site / Ribosomal protein L3, conserved site / Peptidase S8, subtilisin-related / Ribosomal protein L4/L1e, eukaryotic/archaeal, conserved site / Ribosomal protein L25/L23 / 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 / WD40/YVTN repeat-like-containing domain superfamily / Ribosomal S11, conserved site / K homology domain-like, alpha/beta / Ribosomal protein L19/L19e, domain 1 / 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 / WD40 repeat, conserved site / Ubiquitin conserved site / Ribosomal protein L23/L15e core domain superfamily / Ribosomal protein L2, archaeal-type / Ribosomal protein L24e, conserved site / Ribosomal protein L13, conserved site / Ribosomal protein 50S-L18Ae/60S-L20/60S-L18A / Ribosomal protein L4 domain superfamily / Ribosomal protein S19, superfamily / Ribosomal protein S2, flavodoxin-like domain superfamily / Ribosomal protein L31e domain superfamily / Ribosomal protein L39e domain superfamily / Ribosomal protein L19/L19e conserved site / Ribosomal protein S7 domain / Ribosomal protein S15P / Ribosomal protein L15e core domain superfamily / Ribosomal protein L5 eukaryotic/L18 archaeal, C-terminal / 60S ribosomal protein L4, C-terminal domain / 30s ribosomal protein S13, C-terminal / Ribosomal protein S10 domain / Ribosomal protein S2, eukaryotic / 40S ribosomal protein S1/3, eukaryotes / 40S ribosomal protein SA / Ribosomal protein S17, archaeal/eukaryotic / Ribosomal protein L30, central domain, archaeal type / Ribosomal protein L30e, conserved site / Ubiquitin / Ribosomal protein L15e, conserved site / Ribosomal protein L14P, conserved site / Ribosomal protein S17, conserved site / Ribosomal protein L23 / Ribosomal protein L31e, conserved site / Ribosomal protein L39e, conserved site / G-protein beta WD-40 repeat / Ribosomal protein S5 domain 2-type fold / Ribosomal protein S9, conserved site / Ribosomal protein S7, conserved site / Ribosomal protein L5, conserved site / Ribosomal protein L5 domain superfamily / Ribosomal protein S19 conserved site / Ribosomal protein L18e/L15P / Ribosomal protein L18e, conserved site / 60S ribosomal protein L18a/ L20, eukaryotes / Ribosomal protein S8e/ribosomal biogenesis NSA2 / Ribosomal Proteins L2, RNA binding domain / Ribosomal protein L2, C-terminal / Ribosomal protein L2, conserved site / Ribosomal protein S4/S9 / Ribosomal protein L30, N-terminal / Nucleotide-binding alpha-beta plait domain superfamily / 50S ribosomal protein L18Ae/60S ribosomal protein L20 and L18a / Ribosomal protein L29/L35 / Ribosomal protein S3, C-terminal / Ribosomal protein S6e
40S ribosomal protein S28 / 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 S29 / 40S ribosomal protein S4, X isoform / 60S ribosomal protein L7a ...40S ribosomal protein S28 / 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 S29 / 40S ribosomal protein S4, X isoform / 60S ribosomal protein L7a / 40S ribosomal protein S11 / 40S ribosomal protein S13 / 40S ribosomal protein S18 / 40S ribosomal protein S23 / 40S ribosomal protein S14 / 60S ribosomal protein L39 / 60S ribosomal protein L30 / 60S ribosomal protein L24 / 60S ribosomal protein L31 / 40S ribosomal protein S15a / 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 L36a / Receptor of activated protein C kinase 1 / 60S ribosomal protein L32 / 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 / 60S ribosomal protein L11 / 40S ribosomal protein S16 / 60S ribosomal protein L34 / 40S ribosomal protein S8 / 40S ribosomal protein S12 / 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 / 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 / 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 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: 3.72 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: 6om7

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: 0.025
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: : PDB-6om7
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_0597.map.gz / Format: CCP4 / Size: 303.3 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 430 pix.
= 524.6 Å
1.22 Å/pix.
x 430 pix.
= 524.6 Å
1.22 Å/pix.
x 430 pix.
= 524.6 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: 0.025
Minimum - Maximum-0.06245838 - 0.11255686
Average (Standard dev.)0.00044033065 (±0.006970685)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions430430430
Spacing430430430
CellA=B=C: 524.60004 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.221.221.22
M x/y/z430430430
origin x/y/z0.0000.0000.000
length x/y/z524.600524.600524.600
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS430430430
D min/max/mean-0.0620.1130.000

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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, PCSK9-RNC in rotated state with AA tRNA and PE tRNA
Number of components: 1

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Component #1: protein, Drug-like molecule PF846 stalled human ribosome nascent ...

ProteinName: Drug-like molecule PF846 stalled human ribosome nascent chain complex, PCSK9-RNC in rotated state 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: 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: 9564
3D reconstructionResolution: 3.72 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: 91
Output model

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