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

Proc Natl Acad Sci U S A. 2011 Jul 5;108(27):11046-51. doi: 10.1073/pnas.1104850108. Epub 2011 Jun 20.

Abstract

Current views of multidrug (MD) recognition focus on large drug-binding 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Bacillus subtilis / drug effects
  • Bacillus subtilis / genetics*
  • Bacillus subtilis / metabolism
  • Bacterial Proteins / chemistry*
  • Bacterial Proteins / genetics*
  • Bacterial Proteins / metabolism
  • Binding Sites
  • Crystallography, X-Ray
  • Genes, Bacterial*
  • Genes, MDR*
  • Genes, Regulator
  • Hydrogen Bonding
  • Ligands
  • Membrane Transport Proteins / chemistry*
  • Membrane Transport Proteins / genetics*
  • Membrane Transport Proteins / metabolism
  • Models, Molecular
  • Protein Conformation

Substances

  • Bacterial Proteins
  • Ligands
  • Membrane Transport Proteins
  • Bmr protein, Bacillus subtilis

Associated data

  • PDB/3Q1M
  • PDB/3Q2Y
  • PDB/3Q3D
  • PDB/3Q5P
  • PDB/3Q5R
  • PDB/3Q5S