Structural mechanism of inhibition of the rho transcription termination factor by the antibiotic bicyclomycin
Structural mechanism of inhibition of the rho transcription termination factor by the antibiotic bicyclomycin
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DOI：
10.1016/j.str.2004.10.013
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发表时间：
2005-01-01
期刊：
影响因子：
5.7
通讯作者：
Berger, JM
中科院分区：
文献类型：
--
作者：
Skordalakes, E;Brogan, AR;Berger, JM
Rho是一种六聚体RNA/DNA解旋酶/转位酶，可终止细菌中选定基因的转录。自然产生的抗生素双环素(BCM)作为ATP周转的非竞争性抑制剂来破坏这一过程。我们测定了Rho与BCM和两个半合成衍生物5a-(3-formylphenyisulfanyl)-dihydrobicyclomycin(FPDB)和5a-甲酰双环素(FB)的三个独立的X射线晶体结构，其分辨率分别为3.15，3.05和3.15Angstrom。结构表明，BCM及其衍生物是非核苷酸抑制剂，在蛋白质C-末端一半的ATP和RNA结合位点附近的口袋中与Rho相互作用。BCM结合以一种意想不到的机制阻止ATP周转，阻断ATP水解所需的亲核水分子的结合。我们的数据解释了为什么只有BCM的某些成分可以进行修饰，并作为设计新抑制剂的模板。
Rho is a hexameric RNA/DNA helicase/translocase that terminates transcription of select genes in bacteria. The naturally occurring antibiotic, bicyclomycin (BCM), acts as a noncompetitive inhibitor of ATP turnover to disrupt this process. We have determined three independent X-ray crystal structures of Rho complexed with BCM and two semisynthetic derivatives, 5a-(3-formylphenyisulfanyl)-dihydrobicyclomycin (FPDB) and 5a-formylbicyclomycin (FB) to 3.15, 3.05, and 3.15 Angstrom resolution, respectively. The structures show that BCM and its derivatives are nonnucleotide inhibitors that interact with Rho at a pocket adjacent to the ATP and RNA binding sites in the C-terminal half of the protein. BCM association prevents ATP turnover by an unexpected mechanism, occluding the binding of the nucleophilic water molecule required for ATP hydrolysis. Our data explain why only certain elements of BCM have been amenable to modification and serve as a template for the design of new inhibitors.