5ndw | pdb_00005ndw
Crystal structure of aminoglycoside TC007 bound to the yeast 80S ribosome
Structural highlights
Function[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). [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.[1] [RS6A_YEAST] Involved in nucleolar processing of pre-18S ribosomal RNA and ribosome assembly.[2] [RL37A_YEAST] Binds to the 23S rRNA (By similarity). [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.[3] [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.[4] [RS9A_YEAST] Involved in nucleolar processing of pre-18S ribosomal RNA and ribosome assembly.[5] [RL4A_YEAST] Participates in the regulation of the accumulation of its own mRNA.[6] [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).[7] 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.[8] [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.[9] [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.[10] [11] [RL5_YEAST] Binds 5S RNA and is required for 60S subunit assembly. [RS7A_YEAST] Involved in nucleolar processing of pre-18S ribosomal RNA and ribosome assembly.[12] [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.[13] [14] [RL25_YEAST] This protein binds to a specific region on the 26S rRNA. [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.[15] [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] [RL11B_YEAST] Binds to 5S ribosomal RNA. [RS14B_YEAST] Involved in nucleolar processing of pre-18S ribosomal RNA and ribosome assembly.[16] Publication Abstract from PubMedAminoglycosides 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[17] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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