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-Structure paper
タイトル | Structural Basis of Transcription Inhibition by Fidaxomicin (Lipiarmycin A3). |
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ジャーナル・号・ページ | Mol Cell, Vol. 70, Issue 1, Page 60-71.e15, Year 2018 |
掲載日 | 2018年4月5日 |
著者 | Wei Lin / Kalyan Das / David Degen / Abhishek Mazumder / Diego Duchi / Dongye Wang / Yon W Ebright / Richard Y Ebright / Elena Sineva / Matthew Gigliotti / Aashish Srivastava / Sukhendu Mandal / Yi Jiang / Yu Liu / Ruiheng Yin / Zhening Zhang / Edward T Eng / Dennis Thomas / Stefano Donadio / Haibo Zhang / Changsheng Zhang / Achillefs N Kapanidis / Richard H Ebright / |
PubMed 要旨 | 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 ...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-Å 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. |
リンク | Mol Cell / PubMed:29606590 / PubMed Central |
手法 | EM (単粒子) / X線回折 |
解像度 | 3.52 - 3.8 Å |
構造データ | EMDB-4230, PDB-6fbv: PDB-6asg: |
化合物 | ChemComp-ZN: ChemComp-MG: ChemComp-FI8: ChemComp-HOH: |
由来 |
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キーワード | TRANSCRIPTION / Thermus thermophilus / RNA polymerase core enzyme / Lipiarmycin / RNA pol / RNAP / inhibitor / drug / Clostridium difficile / ANTIBIOTIC / Tiacumicin B / CCDC 114782 |