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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Direct crosslinking of the antitumor antibiotic sparsomycin, and its derivatives, to A2602 in the peptidyl ,transferase center of 23S-like rRNA within ribosome-tRNA complexes
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Direct crosslinking of the antitumor antibiotic sparsomycin, and its derivatives, to A2602 in the peptidyl ,transferase center of 23S-like rRNA within ribosome-tRNA complexes

机译：抗肿瘤抗生素sparsomycin及其衍生物直接交联到核糖体-tRNA复合物中23S样rRNA的肽基转移酶中心的A2602

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摘要

The antitumor antibiotic sparsomycin is a universal and potent inhibitor of peptide bond formation and selectively acts on several human tumors. It binds to the ribosome strongly, at an unknown site, in the presence of an N-blocked donor tRNA substrate, which it stabilizes on the ribosome. Its site of action was investigated by inducing a crosslink between sparsomycin and bacterial, archaeal, and eukaryotic ribosomes complexed with P-site-bound tRNA, on irradiating with low energy ultraviolct light (at 365 nm). The crosslink was localized exclusively to the universally conserved nucleotide A2602 within the peptidyl transferase loop region of 23S-Iike rRNA by using a combination of a primer extension approacb, RNase H fragment analysis, aud crosslinking with radioactive [125] phenol-alanine-sparsomycin. Crosslinking or several sparsomycin derivatives, modified near the sulfoxy group implicated the modified tracil residue in the rRNA crosslink. The yield of the antibiotic crosslink was weak in the presence of deacylated tRNA and strong in the presence of an N-blocked P-site-bound tRNA which, as was shown earlier, increases the accessibility of A2602 on the ribosome. We infer that both A2602 and its induced conformational switch are critically important both for the peptidyl transfer reaction and for antibiotic inhibition. This supposi- tion is reinforced by the observation that other antibiotics that can prevent peptide bond formation in viro inhibit, to different degrees, formation of the crosslink.
机译：抗肿瘤抗生素Sparsomycin是一种普遍有效的肽键形成抑制剂，可选择性作用于多种人类肿瘤。在存在N受体供体tRNA底物的情况下，它在未知位点与核糖体牢固结合，并稳定在核糖体上。通过用低能紫外线（365 nm）照射，诱导稀疏霉素与结合P位点的tRNA的细菌，古细菌和真核核糖体之间的交联来研究其作用位点。通过使用引物延伸方法，RNase H片段分析，与放射性[125]苯丙氨酸-丙氨酸-sparsomycin进行音频交联，将交联专门定位在23S-Iike rRNA肽基转移酶环区内的通用保守核苷酸A2602上。在硫氧基附近修饰的交联键或几种Sparsomycin衍生物涉及rRNA交联键中修饰的tracil残基。如前所述，在脱酰基tRNA的存在下，抗生素交联的产量很弱，而在N阻断的P位点结合的tRNA的存在下，抗生素交联的产量却很强，这增加了A2602在核糖体上的可及性。我们推断，A2602及其诱导的构象转换对于肽基转移反应和抗生素抑制都至关重要。观察到其他可以阻止病毒体内肽键形成的抗生素在不同程度上抑制了交联的形成，这进一步证实了这种假设。

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