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; Srivastava, A; Mandal, S; Jiang, Y; Liu, Y; Yin, RH; Zhang, ZN; Eng, ET; Thomas, D; Donadio, S; Zhang, HB; Zhang, CS; Kapanidis, AN; Ebright, RH; kalyan.das@kuleuven.be; ebright@waksman.rutgers.edu
2018
发表期刊MOLECULAR CELL
卷号70期号:1页码:60-+
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.
部门归属[Lin, Wei; Degen, David; Mazumder, Abhishek; Wang, Dongye; Ebright, Yon W.; Ebright, Richard Y.; Sineva, Elena; Gigliotti, Matthew; Srivastava, Aashish; Mandal, Sukhendu; Jiang, Yi; Liu, Yu; Yin, Ruiheng; Ebright, Richard H.] Rutgers State Univ, Waksman Inst, Piscataway, NJ 08854 USA; [Lin, Wei; Degen, David; Mazumder, Abhishek; Wang, Dongye; Ebright, Yon W.; Ebright, Richard Y.; Sineva, Elena; Gigliotti, Matthew; Mandal, Sukhendu; Jiang, Yi; Liu, Yu; Yin, Ruiheng; Ebright, Richard H.] Rutgers State Univ, Dept Chem, Piscataway, NJ 08854 USA; [Das, Kalyan] Katholieke Univ Leuven, Rega Inst, B-3000 Leuven, Belgium; [Das, Kalyan] Katholieke Univ Leuven, Dept Microbiol & Immunol, B-3000 Leuven, Belgium; [Duchi, Diego; Kapanidis, Achillefs N.] Univ Oxford, Dept Phys, Oxford OX1 3PU, England; [Zhang, Zhening; Eng, Edward T.] New York Struct Biol Ctr, Simons Electron Microscopy Ctr, Natl Resource Automated Mol Microscopy, New York, NY 10027 USA; [Thomas, Dennis] Rutgers State Univ, Ctr Integrat Prote, Piscataway, NJ 08854 USA; [Donadio, Stefano] NAICONS Srl, I-20139 Milan, Italy; [Zhang, Haibo; Zhang, Changsheng] Chinese Acad Sci, South China Sea Inst Oceanol, Guangzhou 510301, Guangdong, Peoples R China
学科领域Biochemistry & Molecular Biology ; Cell Biology
资助项目LMB
文献类型期刊论文
条目标识符http://ir.scsio.ac.cn/handle/344004/16968
专题中科院海洋生物资源可持续利用重点实验室
通讯作者kalyan.das@kuleuven.be; ebright@waksman.rutgers.edu
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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@waksman.rutgers.edu.(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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