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Structure of the transcriptional regulator LmrR and its mechanism of multidrug recognition

Madoori, P. K., Agustiandari, H., Driessen, A. J. M. & Thunnissen, A-M. W. H., 21-Jan-2009, In : EMBO Journal. 28, 2, p. 156-166 11 p.

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  • Structure of the transcriptional regulator LmrR and its mechanism of multidrug recognition

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DOI

LmrR is a PadR-related transcriptional repressor that regulates the production of LmrCD, a major multidrug ABC transporter in Lactococcus lactis. Transcriptional regulation is presumed to follow a drug-sensitive induction mechanism involving the direct binding of transporter ligands to LmrR. Here, we present crystal structures of LmrR in an apo state and in two drug-bound states complexed with Hoechst 33342 and daunomycin. LmrR shows a common topology containing a typical beta-winged helix-turn-helix domain with an additional C-terminal helix involved in dimerization. Its dimeric organization is highly unusual with a flat-shaped hydrophobic pore at the dimer centre serving as a multidrug-binding site. The drugs bind in a similar manner with their aromatic rings sandwiched in between the indole groups of two dimer-related tryptophan residues. Multidrug recognition is facilitated by conformational plasticity and the absence of drug-specific hydrogen bonds. Combined analyses using site-directed mutagenesis, fluorescence-based drug binding and protein-DNA gel shift assays reveal an allosteric coupling between the multidrug- and DNA-binding sites of LmrR that most likely has a function in the induction mechanism.

Original languageEnglish
Pages (from-to)156-166
Number of pages11
JournalEMBO Journal
Volume28
Issue number2
Publication statusPublished - 21-Jan-2009

    Keywords

  • bacterial multidrug transcription factors, multidrug recognition, LmrR, PadR, protein structure, CRYSTAL-STRUCTURES, SEQUENCE ALIGNMENTS, LACTOCOCCUS-LACTIS, PROTEIN, TRANSPORTER, REFINEMENT, RESISTANCE, ACTIVATOR, EXPRESSION, REVEALS

ID: 1824523