Dynamic multidrug recognition by multidrug transcriptional repressor LmrR

Sci Rep. 2014 Nov 18;4:6922. doi: 10.1038/srep06922.

Abstract

LmrR is a multidrug transcriptional repressor that controls the expression of a major multidrug transporter, LmrCD, in Lactococcus lactis. However, the molecular mechanism by which LmrR binds to structurally unrelated compounds and is released from the promoter region remains largely unknown. Here, we structurally and dynamically characterized LmrR in the apo, compound-bound and promoter-bound states. The compound-binding site of LmrR exhibits ps-μs dynamics in the apo state, and compound ligation shifts the preexisting conformational equilibrium to varying extents to achieve multidrug recognition. Meanwhile, the compound binding induces redistribution of ps-ns dynamics to the allosteric sites, which entropically favors the high-affinity recognition. Furthermore, the reciprocal compound/promoter binding by LmrR is achieved by the incompatible conformational ensembles between the compound- and promoter-bound states. Collectively, the data show how LmrR can dynamically exert its functions through promiscuous multi-target interactions, in a manner that cannot be understood by a static structural view.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology
  • Binding Sites
  • Daunorubicin / chemistry
  • Daunorubicin / pharmacology
  • Drug Resistance, Multiple, Bacterial / genetics*
  • Ethidium / chemistry
  • Ethidium / pharmacology
  • Gene Expression Regulation, Bacterial*
  • Lactococcus lactis / drug effects
  • Lactococcus lactis / genetics*
  • Lactococcus lactis / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Multidrug Resistance-Associated Proteins / chemistry*
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / metabolism
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Conformation
  • Repressor Proteins / chemistry*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Rhodamines / chemistry
  • Rhodamines / pharmacology
  • Transcription, Genetic

Substances

  • Benzimidazoles
  • LmrC protein, Lactococcus lactis
  • LmrD protein, Lactococcus lactis
  • Multidrug Resistance-Associated Proteins
  • Repressor Proteins
  • Rhodamines
  • rhodamine 6G
  • Ethidium
  • bisbenzimide ethoxide trihydrochloride
  • Daunorubicin