Elements of ribosomal drug resistance and specificity

Blaha, Gregor; Polikanov, Yury S.; Steitz, Thomas A.

doi:10.1016/j.sbi.2012.07.016

Cited by 20 publications

(11 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The carboxyterminal tail of L4 extends toward the A-site finger (25S rRNA helix 38) on the solvent interface via eukaryotic ribosomal components (Ben-Shem et al 2011), also suggesting its importance in eukaryotic translation. To initially test the importance of either the internal loop or carboxy-terminal tail of L4 in yeast ribosome function, we tested for hypersensitivity to drugs that inhibit various aspects of translation in vivo (Yonath 2005;Kannan and Mankin 2011;Blaha et al 2012). Interestingly, the growth of both mutants in the presence of translation inhibitors was the same as when the drugs are absent (Fig.…”

Section: Resultsmentioning

confidence: 99%

Deletion of L4 domains reveals insights into the importance of ribosomal protein extensions in eukaryotic ribosome assembly

Gamalinda

Woolford

2014

RNA

View full text Add to dashboard Cite

Numerous ribosomal proteins have a striking bipartite architecture: a globular body positioned on the ribosomal exterior and an internal loop buried deep into the rRNA core. In eukaryotes, a significant number of conserved r-proteins have evolved extra amino-or carboxy-terminal tail sequences, which thread across the solvent-exposed surface. The biological importance of these extended domains remains to be established. In this study, we have investigated the universally conserved internal loop and the eukaryote-specific extensions of yeast L4. We show that in contrast to findings with bacterial L4, deleting the internal loop of yeast L4 causes severely impaired growth and reduced levels of large ribosomal subunits. We further report that while depleting the entire L4 protein blocks early assembly steps in yeast, deletion of only its extended internal loop affects later steps in assembly, revealing a second role for L4 during ribosome biogenesis. Surprisingly, deletion of the entire eukaryotespecific carboxy-terminal tail of L4 has no effect on viability, production of 60S subunits, or translation. These unexpected observations provide impetus to further investigate the functions of ribosomal protein extensions, especially eukaryote-specific examples, in ribosome assembly and function.

show abstract

Section: Resultsmentioning

confidence: 99%

Deletion of L4 domains reveals insights into the importance of ribosomal protein extensions in eukaryotic ribosome assembly

Gamalinda

Woolford

2014

RNA

View full text Add to dashboard Cite

show abstract

“…A look at the bacterial world only confirms the centrality of rRNA. The many ribosome-directed antibiotics that microorganisms have fashioned to war against one another selectively bind to rRNA rather than protein, detecting nucleotide differences that allow them to discriminate against the invader (Blaha et al, 2012).…”

Section: Rule 4 Ribosomal Rna Is a Scaffold-then A Catalystmentioning

confidence: 99%

The Noncoding RNA Revolution—Trashing Old Rules to Forge New Ones

Cech

Steitz

2014

Cell

2,123

1,548

View full text Add to dashboard Cite

Noncoding RNAs (ncRNAs) accomplish a remarkable variety of biological functions. They regulate gene expression at the levels of transcription, RNA processing, and translation. They protect genomes from foreign nucleic acids. They can guide DNA synthesis or genome rearrangement. For ribozymes and riboswitches, the RNA structure itself provides the biological function, but most ncRNAs operate as RNA-protein complexes, including ribosomes, snRNPs, snoRNPs, telomerase, microRNAs, and long ncRNAs. Many, though not all, ncRNAs exploit the power of base pairing to selectively bind and act on other nucleic acids. Here, we describe the pathway of ncRNA research, where every established "rule" seems destined to be overturned.

show abstract

“…Specific elements of the tunnel monitor the amino acid sequence of the nascent polypeptide chain, and arrest of translation may occur in response to particular drugs or metabolites (82,83). The NPET is the target for many clinically important antibiotics (23,27,54,59) and its alteration can lead to antibiotic resistance in pathogenic bacteria (84)(85)(86)(87). Ketolides are semi-synthetic derivatives of macrolides in which the sugar in position C3 is replaced with a keto group.…”

Section: Antibiotics That Bind In the Npetmentioning

confidence: 99%

Ribosome-Targeting Antibiotics: Modes of Action, Mechanisms of Resistance, and Implications for Drug Design

Lin

Zhou

Steitz

et al. 2018

Annu. Rev. Biochem.

243

200

View full text Add to dashboard Cite

Genetic information is translated into proteins by the ribosome. Structural studies of the ribosome and of its complexes with factors and inhibitors have provided invaluable information on the mechanism of protein synthesis. Ribosome inhibitors are among the most successful antimicrobial drugs and constitute more than half of all medicines used to treat infections. However, bacterial infections are becoming increasingly difficult to treat because the microbes have developed resistance to the most effective antibiotics, creating a major public health care threat. This has spurred a renewed interest in structure-function studies of protein synthesis inhibitors, and in few cases, compounds have been developed into potent therapeutic agents against drug-resistant pathogens. In this review, we describe the modes of action of many ribosome-targeting antibiotics, highlight the major resistance mechanisms developed by pathogenic bacteria, and discuss recent advances in structure-assisted design of new molecules.

show abstract

Elements of ribosomal drug resistance and specificity

Cited by 20 publications

References 61 publications

Deletion of L4 domains reveals insights into the importance of ribosomal protein extensions in eukaryotic ribosome assembly

Deletion of L4 domains reveals insights into the importance of ribosomal protein extensions in eukaryotic ribosome assembly

The Noncoding RNA Revolution—Trashing Old Rules to Forge New Ones

Ribosome-Targeting Antibiotics: Modes of Action, Mechanisms of Resistance, and Implications for Drug Design

Contact Info

Product

Resources

About