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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 dataPF846 stalled human ribosome nascent chain complex (PCSK9-RNC) in rotated state with AA tRNA and PE tRNA; map is sharpened.
Sample
  • Complex: Drug-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


low-density lipoprotein particle receptor catabolic process / negative regulation of receptor-mediated endocytosis involved in cholesterol transport / extrinsic component of external side of plasma membrane / negative regulation of sodium ion import across plasma membrane / PCSK9-LDLR complex / PCSK9-AnxA2 complex / negative regulation of receptor recycling / apolipoprotein receptor binding / very-low-density lipoprotein particle binding / positive regulation of low-density lipoprotein particle receptor catabolic process ...low-density lipoprotein particle receptor catabolic process / negative regulation of receptor-mediated endocytosis involved in cholesterol transport / extrinsic component of external side of plasma membrane / negative regulation of sodium ion import across plasma membrane / PCSK9-LDLR complex / PCSK9-AnxA2 complex / negative regulation of receptor recycling / apolipoprotein receptor binding / very-low-density lipoprotein particle binding / positive regulation of low-density lipoprotein particle receptor catabolic process / low-density lipoprotein particle binding / LDL clearance / lipoprotein metabolic process / very-low-density lipoprotein particle receptor binding / embryonic brain development / translation at presynapse / exit from mitosis / negative regulation of receptor internalization / eukaryotic 80S initiation complex / negative regulation of protein neddylation / response to insecticide / optic nerve development / COPII-coated ER to Golgi transport vesicle / regulation of translation involved in cellular response to UV / axial mesoderm development / negative regulation of formation of translation preinitiation complex / regulation of G1 to G0 transition / ribosomal protein import into nucleus / negative regulation of endoplasmic reticulum unfolded protein response / sodium channel inhibitor activity / oxidized pyrimidine DNA binding / response to TNF agonist / positive regulation of base-excision repair / protein-DNA complex disassembly / positive regulation of respiratory burst involved in inflammatory response / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage / positive regulation of gastrulation / endolysosome membrane / 90S preribosome assembly / protein tyrosine kinase inhibitor activity / retinal ganglion cell axon guidance / positive regulation of endodeoxyribonuclease activity / IRE1-RACK1-PP2A complex / nucleolus organization / positive regulation of Golgi to plasma membrane protein transport / negative regulation of low-density lipoprotein particle clearance / TNFR1-mediated ceramide production / negative regulation of DNA repair / signaling receptor inhibitor activity / negative regulation of RNA splicing / GAIT complex / positive regulation of DNA damage response, signal transduction by p53 class mediator / TORC2 complex binding / alpha-beta T cell differentiation / G1 to G0 transition / supercoiled DNA binding / neural crest cell differentiation / NF-kappaB complex / lysosomal transport / cysteine-type endopeptidase activator activity involved in apoptotic process / oxidized purine DNA binding / middle ear morphogenesis / positive regulation of ubiquitin-protein transferase activity / triglyceride metabolic process / negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide / regulation of establishment of cell polarity / negative regulation of bicellular tight junction assembly / ubiquitin-like protein conjugating enzyme binding / negative regulation of phagocytosis / rRNA modification in the nucleus and cytosol / erythrocyte homeostasis / Formation of the ternary complex, and subsequently, the 43S complex / low-density lipoprotein particle receptor binding / cytoplasmic side of rough endoplasmic reticulum membrane / laminin receptor activity / negative regulation of ubiquitin protein ligase activity / protein kinase A binding / ion channel inhibitor activity / homeostatic process / Ribosomal scanning and start codon recognition / pigmentation / Translation initiation complex formation / positive regulation of mitochondrial depolarization / macrophage chemotaxis / lung morphogenesis / positive regulation of T cell receptor signaling pathway / fibroblast growth factor binding / negative regulation of Wnt signaling pathway / positive regulation of natural killer cell proliferation / monocyte chemotaxis / protein autoprocessing / positive regulation of activated T cell proliferation / negative regulation of translational frameshifting / TOR signaling / Protein hydroxylation / BH3 domain binding / SARS-CoV-1 modulates host translation machinery / iron-sulfur cluster binding / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway
Similarity search - Function
Proprotein convertase subtilisin/kexin type 9, C-terminal domain 3 / Proprotein convertase subtilisin/kexin type 9, C-terminal domain 2 / Proprotein convertase subtilisin/kexin type 9, C-terminal domain 1 / Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain / Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain / Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain / Proteinase K-like catalytic domain / Peptidase S8 propeptide/proteinase inhibitor I9 / Peptidase inhibitor I9 / 40S ribosomal protein SA ...Proprotein convertase subtilisin/kexin type 9, C-terminal domain 3 / Proprotein convertase subtilisin/kexin type 9, C-terminal domain 2 / Proprotein convertase subtilisin/kexin type 9, C-terminal domain 1 / Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain / Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain / Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain / Proteinase K-like catalytic domain / Peptidase S8 propeptide/proteinase inhibitor I9 / Peptidase inhibitor I9 / 40S ribosomal protein SA / Ribosomal protein L6, N-terminal / Ribosomal protein L6, N-terminal domain / 40S ribosomal protein SA, C-terminal domain / 40S ribosomal protein SA C-terminus / Ubiquitin-like protein FUBI / Peptidase S8 propeptide/proteinase inhibitor I9 superfamily / : / Ribosomal protein L30e / Ribosomal protein L28e / Ribosomal L15/L27a, N-terminal / Ribosomal protein L23 / Ribosomal protein L2, archaeal-type / Ribosomal L28e/Mak16 / Ribosomal L28e protein family / Peptidase S8, subtilisin-related / Serine proteases, subtilase domain profile. / Peptidase S8/S53 domain superfamily / Subtilase family / Peptidase S8/S53 domain / metallochaperone-like domain / TRASH domain / : / Ribosomal protein S26e signature. / Ribosomal protein L41 / Ribosomal protein L41 / Ribosomal protein S21e, conserved site / Ribosomal protein S21e signature. / Ribosomal protein S26e / Ribosomal protein S26e superfamily / Ribosomal protein S26e / Ribosomal protein L13e, conserved site / : / Ribosomal protein L13e signature. / Ribosomal protein S12e signature. / Ribosomal protein L29e / Ribosomal L29e protein family / Ribosomal protein S12e / Small (40S) ribosomal subunit Asc1/RACK1 / Ribosomal protein S5, eukaryotic/archaeal / Ribosomal protein L27e, conserved site / Ribosomal protein L27e signature. / Ribosomal protein S21e / Ribosomal protein S21e superfamily / Ribosomal protein S21e / Ribosomal protein L22e / Ribosomal protein L22e superfamily / Ribosomal L22e protein family / Ribosomal protein S19e, conserved site / Ribosomal protein S19e signature. / Ribosomal protein S2, eukaryotic / Ribosomal protein L38e / Ribosomal protein L38e superfamily / Ribosomal L38e protein family / Ribosomal protein L10e, conserved site / Ribosomal protein L10e signature. / Ribosomal protein L19, eukaryotic / : / Ribosomal protein L10e / Ribosomal protein L6e signature. / Ribosomal protein L24e, conserved site / Ribosomal protein L24e signature. / Ribosomal protein L13e / S27a-like superfamily / Ribosomal protein L13e / 40S Ribosomal protein S10 / Ribosomal protein L44e signature. / Ribosomal protein L19/L19e conserved site / Ribosomal protein L19e signature. / 60S ribosomal protein L18a/ L20, eukaryotes / Plectin/S10, N-terminal / Plectin/S10 domain / : / Ribosomal protein S7e signature. / Ribosomal protein L34e, conserved site / Ribosomal protein L34e signature. / Ribosomal protein S10, eukaryotic/archaeal / : / Ribosomal protein L5 eukaryotic, C-terminal / Ribosomal L18 C-terminal region / Ribosomal protein S30 / Ribosomal protein S30 / Ribosomal protein L23/L25, N-terminal / Ribosomal protein L23, N-terminal domain / Ribosomal protein L44e / Ribosomal protein S17e, conserved site / Ribosomal protein L44 / Ribosomal L40e family / Ribosomal protein S17e signature. / Ribosomal protein S25 / S25 ribosomal protein
Similarity search - Domain/homology
FAU ubiquitin like and ribosomal protein S30 fusion / Small ribosomal subunit protein eS17 / Small ribosomal subunit protein uS2 / 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 ...FAU ubiquitin like and ribosomal protein S30 fusion / Small ribosomal subunit protein eS17 / Small ribosomal subunit protein uS2 / 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 / Proprotein convertase subtilisin/kexin type 9 / Large ribosomal subunit protein uL14 / Large ribosomal subunit protein eL36
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.72 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: 0.025
  • 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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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_0597.png

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)
AnnotationPF846 stalled human ribosome nascent chain complex (PCSK9-RNC) in rotated state with AA tRNA and PE tRNA; map is sharpened.
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

Histogram

Histogram (log scale)
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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Additional map: PF846 stalled human ribosome nascent chain complex (PCSK9-RNC)...

Fileemd_0597_additional.map
AnnotationPF846 stalled human ribosome nascent chain complex (PCSK9-RNC) in rotated state with AA 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_0597_half_map_1.map
AnnotationHalf map of PF846 stalled human ribosome nascent chain complex (PCSK9-RNC) in rotated state with AA 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_0597_half_map_2.map
AnnotationHalf map of PF846 stalled human ribosome nascent chain complex (PCSK9-RNC) in rotated state with AA 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 : 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
Components
  • Complex: Drug-like molecule PF846 stalled human ribosome nascent chain complex, PCSK9-RNC in rotated state with AA tRNA and PE tRNA

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Supramolecule #1: Drug-like molecule PF846 stalled human ribosome nascent chain com...

SupramoleculeName: Drug-like molecule PF846 stalled human ribosome nascent chain complex, PCSK9-RNC in rotated state with AA 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: 4 K

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Electron microscopy

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

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.72 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 9564
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Overall B value: 91
Output model

PDB-6om7:
Human ribosome nascent chain complex (PCSK9-RNC) stalled by a drug-like small molecule with AA and PE tRNAs

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