Ryu D H, Rando R R
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Bioorg Med Chem. 2001 Oct;9(10):2601-8. doi: 10.1016/s0968-0896(01)00034-7.
The 16S bacterial ribosomal A-site decoding rRNA region is thought to be the pharmacological target for the aminoglycoside antibiotics. The clinical utility of aminoglycosides could possibly depend on the preferential binding of these drugs to the prokaryotic A-site versus the corresponding A-site from eukaryotes. However, quantitative aminoglycoside binding experiments reported here on prokaryotic and eukaryotic A-site RNA constructs show that there is little in the way of differential binding affinities of aminoglycosides for the two targets. The largest difference in affinity is 4-fold in the case of neomycin, with the prokaryotic A-site construct exhibiting the higher binding affinity. Mutational studies revealed that decoding region constructs retaining elements of non-Watson-Crick (WC) base pairing, specifically bound aminoglycosides with affinities in the muM range. These studies are consistent with the idea that aminoglycoside antibiotics can specifically bind to RNA molecules as long as the latter have non-A form structural elements allowing access of aminoglycosides to the narrow major groove.
16S细菌核糖体A位点解码rRNA区域被认为是氨基糖苷类抗生素的药理学靶点。氨基糖苷类药物的临床效用可能取决于这些药物对原核生物A位点与真核生物相应A位点的优先结合。然而，此处报道的关于原核生物和真核生物A位点RNA构建体的定量氨基糖苷类结合实验表明，氨基糖苷类药物对这两个靶点的结合亲和力差异不大。在新霉素的情况下，亲和力的最大差异为4倍，原核生物A位点构建体表现出更高的结合亲和力。突变研究表明，保留非沃森-克里克（WC）碱基配对元件的解码区域构建体与氨基糖苷类药物的结合亲和力在微摩尔范围内。这些研究与以下观点一致：只要RNA分子具有允许氨基糖苷类药物进入狭窄大沟的非A形式结构元件，氨基糖苷类抗生素就能特异性结合到RNA分子上。
