6ASG

Crystal structure of Thermus thermophilus RNA polymerase core enzyme

Summary for 6ASG

• Entry DOI: 10.2210/pdb6asg/pdb
• Descriptor: DNA-directed RNA polymerase subunit beta, DNA-directed RNA polymerase subunit beta', DNA-directed RNA polymerase subunit alpha, ... (6 entities in total)
• Functional Keywords: thermus thermophilus, rna polymerase core enzyme, transcription
• Biological source: Thermus thermophilus (strain HB8 / ATCC 27634 / DSM 579); More
• Total number of polymer chains: 5
• Total formula weight: 378234.70

Authors

Liu, Y.,Lin, W.,Ying, R.,Ebright, R.H. (deposition date: 2017-08-24, release date: 2018-04-11, Last modification date: 2023-10-04)

Primary citation

Lin, W.,Das, K.,Degen, D.,Mazumder, A.,Duchi, D.,Wang, D.,Ebright, Y.W.,Ebright, R.Y.,Sineva, E.,Gigliotti, M.,Srivastava, A.,Mandal, S.,Jiang, Y.,Liu, Y.,Yin, R.,Zhang, Z.,Eng, E.T.,Thomas, D.,Donadio, S.,Zhang, H.,Zhang, C.,Kapanidis, A.N.,Ebright, R.H.
Structural Basis of Transcription Inhibition by Fidaxomicin (Lipiarmycin A3).
Mol. Cell, 70:60-71.e15, 2018

PubMed Abstract: 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.

PubMed: 29606590
DOI: 10.1016/j.molcel.2018.02.026

Experimental method

X-RAY DIFFRACTION (3.8 Å)