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	Structural Basis of Transcription Inhibition by Fidaxomicin (Lipiarmycin A3)
	Lin, W; Das, K; Degen, D; Mazumder, A; Duchi, D; Wang, DY; Ebright, YW; Ebright, RY; Sineva, E; Gigliotti, M
刊名	MOLECULAR CELL
	2018
卷号	70期号:1页码:60-+
通讯作者	kalyan.das@kuleuven.be ; ebright@waksman.rutgers.edu
英文摘要	Fidaxomicin is an antibacterial drug in clinical use for treatment of Clostridium difficile diarrhea. The active ingredient of fidaxomicin, lipiarmycin A3 (Lpm), functions by inhibiting bacterial RNA polymerase (RNAP). Here we report a cryo-EM structure of Mycobacterium tuberculosis RNAP holoenzyme in complex with Lpm at 3.5-angstrom resolution. The structure shows that Lpm binds at the base of the RNAP "clamp." The structure exhibits an open conformation of the RNAP clamp, suggesting that Lpm traps an open-clamp state. Single-molecule fluorescence resonance energy transfer experiments confirm that Lpm traps an open-clamp state and define effects of Lpm on clamp dynamics. We suggest that Lpm inhibits transcription by trapping an open-clamp state, preventing simultaneous interaction with promoter -10 and -35 elements. The results account for the absence of cross-resistance between Lpm and other RNAP inhibitors, account for structure-activity relationships of Lpm derivatives, and enable structure-based design of improved Lpm derivatives.
学科主题	Biochemistry & Molecular Biology; Cell Biology
内容类型	期刊论文
源URL	[http://ir.scsio.ac.cn/handle/344004/16968]
专题	南海海洋研究所_中科院海洋生物资源可持续利用重点实验室
推荐引用方式 GB/T 7714	Lin, W,Das, K,Degen, D,et al. Structural Basis of Transcription Inhibition by Fidaxomicin (Lipiarmycin A3)[J]. MOLECULAR CELL,2018,70(1):60-+.
APA	Lin, W.,Das, K.,Degen, D.,Mazumder, A.,Duchi, D.,...&Ebright, RH.(2018).Structural Basis of Transcription Inhibition by Fidaxomicin (Lipiarmycin A3).MOLECULAR CELL,70(1),60-+.
MLA	Lin, W,et al."Structural Basis of Transcription Inhibition by Fidaxomicin (Lipiarmycin A3)".MOLECULAR CELL 70.1(2018):60-+.

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