Structural contributions to multidrug recognition in the multidrug resistance (MDR) gene regulator, BmrR

Sharrol Bachas, Christopher Eginton, Drew Gunio, Herschel Wade

Research output: Contribution to journalArticle

Abstract

Current views of multidrug (MD) recognition focus on large drugbinding cavities with flexible elements. However, MD recognition in BmrR is supported by a small, rigid drug-binding pocket. Here, a detailed description of MD binding by the noncanonical BmrR protein is offered through the combined use of X-ray and solution studies. Low shape complementarity, suboptimal packing, and efficient burial of a diverse set of ligands is facilitated by an aromatic docking platform formed by a set of conformationally fixed aromatic residues, hydrophobic pincer pair that locks the different drug structures on the adaptable platform surface, and a trio of acidic residues that enables cation selectivity without much regard to ligand structure. Within the binding pocket is a set of BmrR-derived H-bonding donor and acceptors that solvate a wide range of ligand polar substituent arrangements in a manner analogous to aqueous solvent. Energetic analyses of MD binding by BmrR are consistent with structural data. A common binding orientation for the different BmrR ligands is in line with promiscuous allosteric regulation.

Original languageEnglish (US)
Pages (from-to)11046-11051
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number27
DOIs
StatePublished - Jul 5 2011

Keywords

  • Ligand binding
  • Ligand responsive transcription factor
  • Molecular recognition
  • Multidrug resistance
  • Multispecificity

ASJC Scopus subject areas

  • General

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