Shortly after the discovery of streptomycin, members of the 4,5-linked and 4,6-linked 2-de-oxystreptamine aminoglycoside antibiotics were found in fermentation products of acti-nomycetes (Fig. 6.3) (55, 56). (Althoughmany antibiotics contain aminoglycoside rings and are often referred to as aminoglycosides, the general term "aminoglycoside" will be used here to specifically refer to the 4,5- and the 4,6-subclasses and will be abbreviated AG.) Neomycin B is the prototypical 4,5-linked AG and is composed of four rings, because it is the most effective agent in this class. The genta-micins are the most commonly used 4,6-linked AGs and are composed of only three rings. The 4,6-linked subclass constitutes the majority of the clinically useful agents. The two subclasses have their first two rings in common and work by the identical mechanism of binding to the decoding A-site of 30S, thus causing misreading of mRNA (57). Biochemical probing has firmly established the binding of these agents to the major groove of an asymmetric loop composed in part of several absolutely conserved nucleotides (19). Other poorly conserved nucleotides within this loop also form part of the AG binding pocket and provide the basis for organismal specificity (58).
The structure of paromomycin, a close analog of neomycin B, in complex with rRNA, has been solved multiple times, once by NMR and twice by X-ray crystallography (10, 13, 59). These structures clearly describe the important modes of binding for the 4,5-linked subclass. NMR was also used to solve the structure of gentamicin Cla in complex with its target RNA sequence (60). The orientation of binding is the same—rings I and II from
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