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- PDB-6om7: Human ribosome nascent chain complex (PCSK9-RNC) stalled by a dru... -
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Basic information
Entry | Database: PDB / ID: 6om7 | ||||||
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Title | Human ribosome nascent chain complex (PCSK9-RNC) stalled by a drug-like small molecule with AA and PE tRNAs | ||||||
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![]() | RIBOSOME / selective stalling / drug-like small molecule / human ribosome nascent chain complex | ||||||
Function / homology | ![]() 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 / PCSK9-LDLR complex / PCSK9-AnxA2 complex / : / negative regulation of receptor recycling / apolipoprotein receptor binding / very-low-density lipoprotein particle binding ...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 / PCSK9-LDLR complex / PCSK9-AnxA2 complex / : / negative regulation of receptor recycling / apolipoprotein receptor binding / very-low-density lipoprotein particle binding / negative regulation of low-density lipoprotein particle clearance / low-density lipoprotein particle binding / positive regulation of low-density lipoprotein particle receptor catabolic process / LDL clearance / lipoprotein metabolic process / very-low-density lipoprotein particle receptor binding / embryonic brain development / eukaryotic 80S initiation complex / negative regulation of receptor internalization / : / negative regulation of protein neddylation / negative regulation of endoplasmic reticulum unfolded protein response / oxidized pyrimidine DNA binding / response to TNF agonist / positive regulation of base-excision repair / negative regulation of formation of translation preinitiation complex / regulation of G1 to G0 transition / axial mesoderm development / negative regulation of peptidyl-serine phosphorylation / regulation of signaling receptor activity / positive regulation of respiratory burst involved in inflammatory response / ribosomal protein import into nucleus / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage / 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 / endolysosome membrane / positive regulation of gastrulation / nucleolus organization / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / protein tyrosine kinase inhibitor activity / protein-DNA complex disassembly / 90S preribosome assembly / sodium channel inhibitor activity / IRE1-RACK1-PP2A complex / positive regulation of endodeoxyribonuclease activity / positive regulation of Golgi to plasma membrane protein transport / translation at postsynapse / signaling receptor inhibitor activity / TNFR1-mediated ceramide production / negative regulation of DNA repair / negative regulation of RNA splicing / mammalian oogenesis stage / positive regulation of DNA damage response, signal transduction by p53 class mediator / GAIT complex / A band / supercoiled DNA binding / activation-induced cell death of T cells / TORC2 complex binding / neural crest cell differentiation / alpha-beta T cell differentiation / G1 to G0 transition / NF-kappaB complex / oxidized purine DNA binding / cysteine-type endopeptidase activator activity involved in apoptotic process / middle ear morphogenesis / negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide / exit from mitosis / ubiquitin-like protein conjugating enzyme binding / regulation of establishment of cell polarity / translation at presynapse / positive regulation of ubiquitin-protein transferase activity / lysosomal transport / rRNA modification in the nucleus and cytosol / Formation of the ternary complex, and subsequently, the 43S complex / negative regulation of phagocytosis / erythrocyte homeostasis / triglyceride metabolic process / optic nerve development / cytoplasmic side of rough endoplasmic reticulum membrane / laminin receptor activity / low-density lipoprotein particle receptor binding / protein kinase A binding / retinal ganglion cell axon guidance / negative regulation of ubiquitin protein ligase activity / pigmentation / Ribosomal scanning and start codon recognition / ion channel inhibitor activity / homeostatic process / Translation initiation complex formation / response to aldosterone / positive regulation of mitochondrial depolarization / COPII-coated ER to Golgi transport vesicle / positive regulation of T cell receptor signaling pathway / macrophage chemotaxis / positive regulation of activated T cell proliferation / fibroblast growth factor binding / negative regulation of Wnt signaling pathway / lung morphogenesis / monocyte chemotaxis / negative regulation of translational frameshifting Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.7 Å | ||||||
![]() | Li, W. / Cate, J.H.D. | ||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
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Structure viewer | Molecule: ![]() ![]() |
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PDBx/mmCIF format | ![]() | 4.7 MB | Display | ![]() |
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PDB format | ![]() | Display | ![]() | |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Summary document | ![]() | 2.5 MB | Display | ![]() |
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Full document | ![]() | 2.7 MB | Display | |
Data in XML | ![]() | 377.1 KB | Display | |
Data in CIF | ![]() | 628.7 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 0597MC ![]() 0526C ![]() 0596C ![]() 0598C ![]() 0599C ![]() 0600C ![]() 0601C ![]() 6oleC ![]() 6olfC ![]() 6olgC ![]() 6oliC ![]() 6olzC ![]() 6om0C M: map data used to model this data C: citing same article ( |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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1 |
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Components
-RNA chain , 7 types, 7 molecules S2DEtvwu
#1: RNA chain | Mass: 553505.062 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() |
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#38: RNA chain | Mass: 50449.812 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() |
#39: RNA chain | Mass: 38998.078 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() |
#79: RNA chain | Mass: 1168718.500 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() |
#80: RNA chain | Mass: 24436.508 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() |
#81: RNA chain | Mass: 3193.932 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() |
#82: RNA chain | Mass: 24414.451 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() |
+40S ribosomal protein ... , 32 types, 32 molecules SASBSDSESFSHSISKSLSPSQSRSSSTSUSVSXSaScSdSCSGSJSMSNSOSWSYSZSbSeSf
+60S ribosomal protein ... , 42 types, 42 molecules ABCFGHIJKLMNOPQRSTUVWXYZabcdef...
-Protein / Protein/peptide , 2 types, 2 molecules Sgy
#22: Protein | Mass: 34568.012 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() |
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#83: Protein/peptide | Mass: 2886.409 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() |
-Non-polymers , 4 types, 52 molecules 






#84: Chemical | ChemComp-ZN / #85: Chemical | ChemComp-MG / #86: Chemical | ChemComp-MVM / | #87: Water | ChemComp-HOH / | |
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-Details
Has protein modification | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: Human ribosome nascent chain complex stalled by a drug-like small molecule (PCSK9_RNC) withAA and PP tRNAs Type: RIBOSOME / Entity ID: #1-#83 / Source: NATURAL |
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Source (natural) | Organism: ![]() |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Details: unspecified |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
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Processing
CTF correction | Type: NONE |
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3D reconstruction | Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 9564 / Symmetry type: POINT |