Abstract
Bacterial RNA polymerase (RNAP) holoenzyme initiates transcription by recognizing the conserved –35 and –10 promoter elements that are optimally separated by a 17-bp spacer. The MerR family of transcriptional regulators activate suboptimal 19–20 bp spacer promoters in response to myriad cellular signals, ranging from heavy metals to drug-like compounds. The regulation of transcription by MerR family regulators is not fully understood. Here we report one crystal structure of a multidrug-sensing MerR family regulator EcmrR and nine cryo-electron microscopy structures that capture the EcmrR-dependent transcription process from promoter opening to initial transcription to RNA elongation. These structures reveal that EcmrR is a dual ligand-binding factor that reshapes the suboptimal 19-bp spacer DNA to enable optimal promoter recognition, sustains promoter remodeling to stabilize initial transcribing complexes, and finally dissociates from the promoter to reverse DNA remodeling and facilitate the transition to elongation. Our findings yield a comprehensive model for transcription regulation by MerR family factors and provide insights into the transition from transcription initiation to elongation.
Highlights
Bacterial RNA polymerase (RNAP) holoenzyme initiates transcription by recognizing the conserved –35 and –10 promoter elements that are optimally separated by a 17-bp spacer
The transcription activation is further boosted by a range of structurally diverse drug-like compounds, indicating broad selectivity of ligand binding by EcmrR (Supplementary Fig. 1h)
As with all other members of the MerR family, spacer DNA remodeling is an essential step in EcmrR-mediated transcription activation
Summary
Bacterial RNA polymerase (RNAP) holoenzyme initiates transcription by recognizing the conserved –35 and –10 promoter elements that are optimally separated by a 17-bp spacer. Structures of BmrR and CueR, two MerR family transcriptional regulators that respond to cationic lipophilic drug-like compounds[14] and Cu(I)[15], respectively, revealed that these regulators under-twist and sharply bend the spacer DNA when they are activated by binding to their effectors[11,12]. This local modulation of DNA structure results in shortened distance and rotated angles between the –35 and –10 elements that become readily recognizable by the σ factor. Our study elucidates the dynamic process of EcmrRregulated transcription in detail and suggests a common mechanism utilized by MerR family factors for transcription regulation
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