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{{Large structure}}
 
==Crystal structure of aminoglycoside TC007 bound to the yeast 80S ribosome==
==Crystal structure of aminoglycoside TC007 bound to the yeast 80S ribosome==
<StructureSection load='5ndw' size='340' side='right' caption='[[5ndw]], [[Resolution|resolution]] 3.70&Aring;' scene=''>
<StructureSection load='5ndw' size='340' side='right'caption='[[5ndw]], [[Resolution|resolution]] 3.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5ndw]] is a 158 chain structure with sequence from [http://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae], [http://en.wikipedia.org/wiki/Saccharomyces_cerevisiae_(strain_atcc_204508_/_s288c) Saccharomyces cerevisiae (strain atcc 204508 / s288c)] and [http://en.wikipedia.org/wiki/Saccharomyces_cerevisiae_s288c Saccharomyces cerevisiae s288c]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NDW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NDW FirstGlance]. <br>
<table><tr><td colspan='2'>[[5ndw]] is a 20 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae] and [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae_S288C Saccharomyces cerevisiae S288C]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NDW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5NDW FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8UZ:TC007'>8UZ</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.7&#8491;</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ndw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ndw OCA], [http://pdbe.org/5ndw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ndw RCSB], [http://www.ebi.ac.uk/pdbsum/5ndw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ndw ProSAT]</span></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8UZ:TC007'>8UZ</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5ndw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ndw OCA], [https://pdbe.org/5ndw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ndw RCSB], [https://www.ebi.ac.uk/pdbsum/5ndw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ndw ProSAT]</span></td></tr>
</table>
</table>
{{Large structure}}
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/RS27A_YEAST RS27A_YEAST]] Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, and DNA-damage responses. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling (By similarity).  40S ribosomal protein S31 is a component of the 40S subunit of the ribosome (By similarity). [[http://www.uniprot.org/uniprot/RS21A_YEAST RS21A_YEAST]] Required for the processing of the 20S rRNA-precursor to mature 18S rRNA in a late step of the maturation of 40S ribosomal subunits. Has a physiological role leading to 18S rRNA stability.<ref>PMID:14627813</ref>  [[http://www.uniprot.org/uniprot/RS6A_YEAST RS6A_YEAST]] Involved in nucleolar processing of pre-18S ribosomal RNA and ribosome assembly.<ref>PMID:15590835</ref>  [[http://www.uniprot.org/uniprot/RL37A_YEAST RL37A_YEAST]] Binds to the 23S rRNA (By similarity). [[http://www.uniprot.org/uniprot/RS15_YEAST RS15_YEAST]] Involved in the nuclear export of the small ribosomal subunit. Has a role in the late stage of the assembly of pre-40S particles within the nucleus and controls their export to the cytoplasm.<ref>PMID:15167894</ref>  [[http://www.uniprot.org/uniprot/STM1_YEAST STM1_YEAST]] Binds specifically G4 quadruplex (these are four-stranded right-handed helices, stabilized by guanine base quartets) and purine motif triplex (characterized by a third, antiparallel purine-rich DNA strand located within the major groove of a homopurine stretch of duplex DNA) nucleic acid structures. These structures may be present at telomeres or in rRNAs. Acts with CDC13 to control telomere length homeostasis. Involved in the control of the apoptosis-like cell death.<ref>PMID:15044472</ref>  [[http://www.uniprot.org/uniprot/RS9A_YEAST RS9A_YEAST]] Involved in nucleolar processing of pre-18S ribosomal RNA and ribosome assembly.<ref>PMID:15590835</ref>  [[http://www.uniprot.org/uniprot/RL4A_YEAST RL4A_YEAST]] Participates in the regulation of the accumulation of its own mRNA.<ref>PMID:2065661</ref>  [[http://www.uniprot.org/uniprot/RL401_YEAST RL401_YEAST]] Ubiquitin: exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, and DNA-damage responses. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling (By similarity).<ref>PMID:23169626</ref>  60S ribosomal protein L40: component of the 60S subunit of the ribosome. Ribosomal protein L40 is essential for translation of a subset of cellular transcripts, including stress response transcripts, such as DDR2.<ref>PMID:23169626</ref>  [[http://www.uniprot.org/uniprot/RS2_YEAST RS2_YEAST]] Important in the assembly and function of the 40S ribosomal subunit. Mutations in this protein affects the control of translational fidelity. Involved in nucleolar processing of pre-18S ribosomal RNA and ribosome assembly.<ref>PMID:15590835</ref>  [[http://www.uniprot.org/uniprot/RSSA1_YEAST RSSA1_YEAST]] Required for the assembly and/or stability of the 40S ribosomal subunit. Required for the processing of the 20S rRNA-precursor to mature 18S rRNA in a late step of the maturation of 40S ribosomal subunits.<ref>PMID:9973221</ref> <ref>PMID:14627813</ref>  [[http://www.uniprot.org/uniprot/RL5_YEAST RL5_YEAST]] Binds 5S RNA and is required for 60S subunit assembly. [[http://www.uniprot.org/uniprot/RS7A_YEAST RS7A_YEAST]] Involved in nucleolar processing of pre-18S ribosomal RNA and ribosome assembly.<ref>PMID:15590835</ref>  [[http://www.uniprot.org/uniprot/RS19A_YEAST RS19A_YEAST]] Required for proper maturation of the small (40S) ribosomal subunit. Binds to 40s pre-ribosomal particles, probably required after association of NOC4 but before association of ENP1, TSR1 and RIO2 with 20/21S pre-rRNA.<ref>PMID:16159874</ref> <ref>PMID:17726054</ref> [[http://www.uniprot.org/uniprot/RL25_YEAST RL25_YEAST]] This protein binds to a specific region on the 26S rRNA. [[http://www.uniprot.org/uniprot/GBLP_YEAST GBLP_YEAST]] Located at the head of the 40S ribosomal subunit in the vicinity of the mRNA exit channel, it serves as a scaffold protein that can recruit other proteins to the ribosome. Involved in the negative regulation of translation of a specific subset of proteins.<ref>PMID:15340087</ref> [[http://www.uniprot.org/uniprot/RS18A_YEAST RS18A_YEAST]] Located at the top of the head of the 40S subunit, it contacts several helices of the 18S rRNA (By similarity).[HAMAP-Rule:MF_01315] [[http://www.uniprot.org/uniprot/RL11B_YEAST RL11B_YEAST]] Binds to 5S ribosomal RNA. [[http://www.uniprot.org/uniprot/RS14B_YEAST RS14B_YEAST]] Involved in nucleolar processing of pre-18S ribosomal RNA and ribosome assembly.<ref>PMID:15590835</ref> 
[https://www.uniprot.org/uniprot/RS10A_YEAST RS10A_YEAST]  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Aminoglycosides are chemically diverse, broad-spectrum antibiotics that target functional centers within the bacterial ribosome to impact all four principle stages (initiation, elongation, termination, and recycling) of the translation mechanism. The propensity of aminoglycosides to induce miscoding errors that suppress the termination of protein synthesis supports their potential as therapeutic interventions in human diseases associated with premature termination codons (PTCs). However, the sites of interaction of aminoglycosides with the eukaryotic ribosome and their modes of action in eukaryotic translation remain largely unexplored. Here, we use the combination of X-ray crystallography and single-molecule FRET analysis to reveal the interactions of distinct classes of aminoglycosides with the 80S eukaryotic ribosome. Crystal structures of the 80S ribosome in complex with paromomycin, geneticin (G418), gentamicin, and TC007, solved at 3.3- to 3.7-A resolution, reveal multiple aminoglycoside-binding sites within the large and small subunits, wherein the 6'-hydroxyl substituent in ring I serves as a key determinant of binding to the canonical eukaryotic ribosomal decoding center. Multivalent binding interactions with the human ribosome are also evidenced through their capacity to affect large-scale conformational dynamics within the pretranslocation complex that contribute to multiple aspects of the translation mechanism. The distinct impacts of the aminoglycosides examined suggest that their chemical composition and distinct modes of interaction with the ribosome influence PTC read-through efficiency. These findings provide structural and functional insights into aminoglycoside-induced impacts on the eukaryotic ribosome and implicate pleiotropic mechanisms of action beyond decoding.
 
Aminoglycoside interactions and impacts on the eukaryotic ribosome.,Prokhorova I, Altman RB, Djumagulov M, Shrestha JP, Urzhumtsev A, Ferguson A, Chang CT, Yusupov M, Blanchard SC, Yusupova G Proc Natl Acad Sci U S A. 2017 Dec 5. pii: 1715501114. doi:, 10.1073/pnas.1715501114. PMID:29208708<ref>PMID:29208708</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5ndw" style="background-color:#fffaf0;"></div>
 
==See Also==
*[[Ribosome 3D structures|Ribosome 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Saccharomyces cerevisiae]]
[[Category: Saccharomyces cerevisiae]]
[[Category: Saccharomyces cerevisiae s288c]]
[[Category: Saccharomyces cerevisiae S288C]]
[[Category: Djumagulov, M]]
[[Category: Djumagulov M]]
[[Category: Prokhorova, I]]
[[Category: Prokhorova I]]
[[Category: Urzhumtsev, A]]
[[Category: Urzhumtsev A]]
[[Category: Yusupov, M]]
[[Category: Yusupov M]]
[[Category: Yusupova, G]]
[[Category: Yusupova G]]
[[Category: Aminoglycoside]]
[[Category: Antibiotic]]
[[Category: Eukaryote]]
[[Category: Inhibitor]]
[[Category: Ribosome]]
[[Category: Rna-protein complex]]
[[Category: Translation]]

Latest revision as of 15:49, 15 November 2023

Crystal structure of aminoglycoside TC007 bound to the yeast 80S ribosomeCrystal structure of aminoglycoside TC007 bound to the yeast 80S ribosome

Structural highlights

5ndw is a 20 chain structure with sequence from Saccharomyces cerevisiae and Saccharomyces cerevisiae S288C. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.7Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RS10A_YEAST

Publication Abstract from PubMed

Aminoglycosides are chemically diverse, broad-spectrum antibiotics that target functional centers within the bacterial ribosome to impact all four principle stages (initiation, elongation, termination, and recycling) of the translation mechanism. The propensity of aminoglycosides to induce miscoding errors that suppress the termination of protein synthesis supports their potential as therapeutic interventions in human diseases associated with premature termination codons (PTCs). However, the sites of interaction of aminoglycosides with the eukaryotic ribosome and their modes of action in eukaryotic translation remain largely unexplored. Here, we use the combination of X-ray crystallography and single-molecule FRET analysis to reveal the interactions of distinct classes of aminoglycosides with the 80S eukaryotic ribosome. Crystal structures of the 80S ribosome in complex with paromomycin, geneticin (G418), gentamicin, and TC007, solved at 3.3- to 3.7-A resolution, reveal multiple aminoglycoside-binding sites within the large and small subunits, wherein the 6'-hydroxyl substituent in ring I serves as a key determinant of binding to the canonical eukaryotic ribosomal decoding center. Multivalent binding interactions with the human ribosome are also evidenced through their capacity to affect large-scale conformational dynamics within the pretranslocation complex that contribute to multiple aspects of the translation mechanism. The distinct impacts of the aminoglycosides examined suggest that their chemical composition and distinct modes of interaction with the ribosome influence PTC read-through efficiency. These findings provide structural and functional insights into aminoglycoside-induced impacts on the eukaryotic ribosome and implicate pleiotropic mechanisms of action beyond decoding.

Aminoglycoside interactions and impacts on the eukaryotic ribosome.,Prokhorova I, Altman RB, Djumagulov M, Shrestha JP, Urzhumtsev A, Ferguson A, Chang CT, Yusupov M, Blanchard SC, Yusupova G Proc Natl Acad Sci U S A. 2017 Dec 5. pii: 1715501114. doi:, 10.1073/pnas.1715501114. PMID:29208708[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Prokhorova I, Altman RB, Djumagulov M, Shrestha JP, Urzhumtsev A, Ferguson A, Chang CT, Yusupov M, Blanchard SC, Yusupova G. Aminoglycoside interactions and impacts on the eukaryotic ribosome. Proc Natl Acad Sci U S A. 2017 Dec 5. pii: 1715501114. doi:, 10.1073/pnas.1715501114. PMID:29208708 doi:http://dx.doi.org/10.1073/pnas.1715501114

5ndw, resolution 3.70Å

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