The Ribosomal Protein uL22 Modulates the Shape of the Protein Exit Tunnel

Wekselman, Itai; Zimmerman, Ella; Davidovich, Chen; Belousoff, Matthew J.; Matzov, Donna; Krupkin, Miri; Rozenberg, Haim; Bashan, Anat; Friedlander, Gilgi; Kjeldgaard, Jette Sejer; Ingmer, Hanne; Lindahl, Lasse; Zengel, Janice M.; Yonath, Ada

doi:10.1016/j.str.2017.06.004

Cited by 21 publications

(18 citation statements)

References 66 publications

(113 reference statements)

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“…Importantly, in several cases resistant mechanisms are involved in cellular regulation, such as translation arrest, that can be triggered by the activation of antibiotic-resistance genes (69). Also, alterations in the locations of ribosomal components may cause resistance by reshaping antibiotic binding pockets or their environments (e.g., [69][70][71][72]. Importantly, macrolide binding seems to be involved in cellular processes.…”

Section: Figurementioning

confidence: 99%

A Bright Future for Antibiotics?

Matzov

Bashan²,

Yonath³

2017

Annu. Rev. Biochem.

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Multidrug resistance is a global threat as the clinically available potent antibiotic drugs are becoming exceedingly scarce. For example, increasing drug resistance among gram-positive bacteria is responsible for approximately one-third of nosocomial infections. As ribosomes are a major target for these drugs, they may serve as suitable objects for novel development of next-generation antibiotics. Three-dimensional structures of ribosomal particles from Staphylococcus aureus obtained by X-ray crystallography have shed light on fine details of drug binding sites and have revealed unique structural motifs specific for this pathogenic strain, which may be used for the design of novel degradable pathogen-specific, and hence, environmentally friendly drugs.

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Section: Figurementioning

confidence: 99%

A Bright Future for Antibiotics?

Matzov

Bashan²,

Yonath³

2017

Annu. Rev. Biochem.

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“…These proteins have extended loops that form the wall of the peptide exit tunnel, near the binding site of MLSBK antibiotics. Although these loops do not directly contact ribosome-bound drugs, mutations in them can trigger conformational changes of surrounding rRNA that propagate into the binding sites of MSLBK antibiotics(146).…”

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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.

229

200

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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.

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“…To date, more than 900 protein structures from Deinococcus species have been deposited in the Protein Data Bank, providing valuable information on the mechanisms of the extreme resistance of D. radiodurans . And structural studies of large protein complexes including ribosomal proteins and ribonucleoprotein complexes shed new light on the mechanisms of antibiotic inhibition and RNA degradation [85] , [86] . These proteins, with both commonalities and diversity in structural features, are involved in the efficient repair of DNA damage and strong antioxidation systems.…”

Section: Discussionmentioning

confidence: 99%

Structural features and functional implications of proteins enabling the robustness of Deinococcus radiodurans

Chen

Tang

Hua

et al. 2020

Computational and Structural Biotechnology Journal

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Deinococcus radiodurans can survive under extreme conditions, including high doses of DNA damaging agents and ionizing radiation, desiccation, and oxidative stress. Both the efficient cellular DNA repair machinery and antioxidation systems contribute to the extreme resistance of this bacterium, making it an ideal organism for studying the cellular mechanisms of environmental adaptation. The number of stress-related proteins identified in this bacterium has mushroomed in the past two decades. The newly identified proteins reveal both commonalities and diversity of structure, mechanism, and function, which impact a wide range of cellular functions. Here, we review the unique and general structural features of these proteins and discuss how these studies improve our understanding of the environmental stress adaptation mechanisms of D. radiodurans .

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The Ribosomal Protein uL22 Modulates the Shape of the Protein Exit Tunnel

Abstract: Highlights d Structure of the 50S subunit with a distal erythromycin resistance mutation in uL22 d The mutation triggers substantial conformational changes in the exit tunnel d The rRNA rearrangements propagate to the binding pocket of erythromycin

Cited by 21 publications

References 66 publications

A Bright Future for Antibiotics?

A Bright Future for Antibiotics?

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

Structural features and functional implications of proteins enabling the robustness of Deinococcus radiodurans

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