Molecular recognition of RNA by neomycin and a restricted neomycin derivative
Molecular recognition of RNA by neomycin and a restricted neomycin derivative
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DOI：
10.1002/anie.200500903
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发表时间：
2005-01-01
影响因子：
16.6
通讯作者：
Hermann, T
中科院分区：
文献类型：
--
作者：
Zhao, F;Zhao, Q;Hermann, T
Aminoglycoside antibiotics such as neomycin (1a) and paromomycin (1b) bind to ribosomal RNA (rRNA) at the decoding site and thereby interfere with the accuracy of protein synthesis, ultimately leading to bacterial cell death (Figure 1). In addition to the decoding site in 16S rRNA, several other RNA motifs form well-defined complexes with individual aminoglycosides, which makes these antibiotics excellent model ligands for the study of RNA recognition.[1, 2] The target “promiscuity” of the aminoglycosides has been attributed to two major factors: 1) their highly charged nature, which is responsible for their eletrostatically driven RNA-binding mode and 2) their conformational adaptability. Although rotation around the glycosidic bonds that link the saccharide building blocks is restricted, the remaining limited flexibility explains some adaptability toward diverse RNA targets.[2] This restricted conformational flexibility attenuates the contribution of charged interactions between RNA and the aminoglycosides, resulting in the formation of welldefined drug complexes that are distinct from nonspecific interactions of nucleic acids with flexible polyamines such as spermidine. The term structural electrostatic complementarity has been coined for this promiscuous yet target-specific binding of aminoglycosides to RNA.[2] Aminoglycosides derived from 4, 5-disubstituted 2-deoxystreptamine (2-DOS, ring I), including neomycin (1a) and paromomycin (1b), bind to a variety of RNA sequences. Examination of structurally characterized aminoglycoside complexes reveals that the relative orientation of ringsI and II is very similar, whereas the conformation around the linkages to rings III and IV is significantly variable depending on the RNA target.[3] The apparent rigidity of the ring I/II system underlines the importance of this module for RNA recognition, attested by the fact that the 2-DOS and ring II moieties participate in key interactions that are responsible for target binding in decoding-site complexes with aminoglycosides.[1, 4–6] Whereas higher thermal factors of rings III and IV in the crystal structure of paromomycin might suggest that these sugars generally contribute less to target-specific interactions,[4, 5] the results presented herein suggest that the affinity of neomycin for the cognate decoding-site RNA and thus the antibacterial activity of this compound depend on an exquisitely balanced interplay of all four rings. Previous investigations of aminoglycoside mimetics derived from neamine and paromamine, both of which lack rings III and IV, confirm the key role that the ring I/II core plays in decoding-site binding.[7, 8] In the crystal structure of the related aminoglycoside paromomycin (1b) complexed with bacterial decoding-site RNA,[4, 5] the distance between the 2о-amino group of ring II and the 5оо-C atom of ring III is% 3.7, which suggests that cross-linking these positions may yield an aminoglycoside that retains the decoding-site-bound conformation of the parent drug. To support this hypothesis, we determined the X-ray crystal structures of neomycin (1a), among the most potent aminoglycoside antibiotics of therapeutic relevance, and its conformationally restricted analogue 2 bound to a decoding-site oligonucleotide (Figure 1 a). Herein, we analyze the structural characteristics of both RNA–small-molecule complexes and discuss the structural basis of aminoglycoside ligand affinity along with general implications on the understanding of RNA recognition. For the synthesis of restricted neomycin 2 we devised an intramolecular and regioselective cyclization strategy of an unprotected 5оо-activated neomycin intermediate under highdilution conditions that exploits the …
