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Single particle cryo em structure of Mycobacterium tuberculosis RNA polymerase in complex with FidaxomicinSingle particle cryo em structure of Mycobacterium tuberculosis RNA polymerase in complex with Fidaxomicin
Structural highlights
Function[RPOZ_MYCTU] Promotes RNA polymerase assembly. Latches the N- and C-terminal regions of the beta' subunit thereby facilitating its interaction with the beta and alpha subunits.[1] [RPOA_MYCTU] DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.[HAMAP-Rule:MF_00059][2] [RPOC_MYCTU] DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.[HAMAP-Rule:MF_01322][3] [RPOB_MYCTU] DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.[HAMAP-Rule:MF_01321] [SIGA_MYCTU] Sigma factors are initiation factors that promote the attachment of RNA polymerase to specific initiation sites and are then released. This sigma factor is the primary sigma factor during exponential growth (Probable).[4] [5] [6] Publication Abstract from PubMedFidaxomicin 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-A 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. Structural Basis of Transcription Inhibition by Fidaxomicin (Lipiarmycin A3).,Lin W, Das K, Degen D, Mazumder A, Duchi D, Wang D, Ebright YW, Ebright RY, Sineva E, Gigliotti M, Srivastava A, Mandal S, Jiang Y, Liu Y, Yin R, Zhang Z, Eng ET, Thomas D, Donadio S, Zhang H, Zhang C, Kapanidis AN, Ebright RH Mol Cell. 2018 Apr 5;70(1):60-71.e15. doi: 10.1016/j.molcel.2018.02.026. Epub, 2018 Mar 29. PMID:29606590[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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