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Unconventional Coupling between Ligand Recognition and Allosteric Control in the Multidrug Resistance Gene Regulator, BmrR
Author(s) -
Bachas Sharrol,
Kohrs Bryan,
Wade Herschel
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700017
Subject(s) - allosteric regulation , cooperativity , regulator , ligand (biochemistry) , chemistry , allosteric modulator , cooperative binding , biophysics , coupling (piping) , allosteric enzyme , binding site , computational biology , biology , receptor , biochemistry , gene , materials science , metallurgy
BmrR is a multidrug resistance (MDR) regulator that responds to diverse ligands. To obtain insight into signal recognition, allosteric control, and cooperativity, we used a quantitative in vitro transcription assay to determine the ligand‐dependent activation profiles for a diverse set of cations, zwitterions, and uncharged ligands. As for many other biological switch systems, the data are well described by a modified Hill equation. Parameters extracted from curve fits to the data include L 50 , R MAX and N . We found that L 50 values correlate directly with Δ G BIND values, suggesting that the parameter reflects binding, whereas R MAX and N reflect allosteric control and cooperativity, respectively. Our results suggest unconventional coupling between ligand binding and allosteric control, with weakly interacting ligands exhibiting the highest levels of activation. Such properties are in stark contrast to those often exhibited by biological switch proteins, whereby ligand binding and allostery are tightly coupled, yielding both high selectivity and ultrasensitivity. We propose that weakened coupling, as observed for BmrR, may be important for providing robust activation responses to unrelated ligands. We also propose that other MDR proteins and other polyspecific switch systems will show similar features.