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The Ribosomal A‐site: Decoding, Drug Target, and Disease
Author(s) -
Matt Tanja,
Akbergenov Rashid,
Shcherbakov Dmitry,
Böttger Erik C.
Publication year - 2010
Publication title -
israel journal of chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.908
H-Index - 54
eISSN - 1869-5868
pISSN - 0021-2148
DOI - 10.1002/ijch.201000003
Subject(s) - transfer rna , ribosomal rna , ribosome , aminoglycoside , ribosomal protein , a site , chemistry , genetics , biology , biochemistry , rna , binding site , gene , antibiotics
Abstract Abstract : Accurate decoding is central in protein synthesis. It occurs at the aa‐tRNA decoding site (A‐site) on the small ribosomal subunit to recognize the interactions between the aa‐tRNA anticodon and the mRNA codon. Ribosomal RNA sequence polymorphism in the mitoribosomal A‐site is associated with maternally transmitted deafness and hypersusceptibility to aminoglycoside‐induced ototoxicity. Aminoglycosides, an important class of broad‐range antimicrobial agents, bind to the A‐site of the small ribosomal subunit. These compounds preferentially target the prokaryotic over the eukaryotic ribosome and affect protein synthesis by inducing codon misreading and inhibiting tRNA translocation. The therapeutic use of these compounds is compromised by significant toxicity, in particular ototoxicity. Recent evidence converges on mitochondrial mistranslation as a key element in both mitochondrial rRNA polymorphism‐associated and aminoglycoside‐induced deafness. It constitutes a formidable challenge to build upon this insight and to develop aminoglycosides which are more selective and consequently may not be plagued by mechanism of action related toxicity.