Unconventional Coupling between Ligand Recognition and Allosteric Control in the Multidrug Resistance Gene Regulator, BmrR

Sharrol Bachas, Bryan Kohrs, Herschel Wade

Research output: Contribution to journalArticle

Abstract

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 invitro 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 L50, RMAX and N. We found that L50 values correlate directly with ΔGBIND values, suggesting that the parameter reflects binding, whereas RMAX 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.

Original languageEnglish (US)
JournalChemMedChem
DOIs
StateAccepted/In press - 2017

Fingerprint

MDR Genes
Genes
Ligands
Chemical activation
Switches
P-Glycoproteins
Multiple Drug Resistance
Transcription
Information Systems
Cations
Assays

Keywords

  • Allosterism
  • Biosensors
  • In vitro transcription
  • Molecular recognition
  • Multidrug resistance

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

Cite this

@article{d37960ffd1c14b0d91ab1fcbe261c135,
title = "Unconventional Coupling between Ligand Recognition and Allosteric Control in the Multidrug Resistance Gene Regulator, BmrR",
abstract = "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 invitro 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 L50, RMAX and N. We found that L50 values correlate directly with ΔGBIND values, suggesting that the parameter reflects binding, whereas RMAX 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.",
keywords = "Allosterism, Biosensors, In vitro transcription, Molecular recognition, Multidrug resistance",
author = "Sharrol Bachas and Bryan Kohrs and Herschel Wade",
year = "2017",
doi = "10.1002/cmdc.201700017",
language = "English (US)",
journal = "ChemMedChem",
issn = "1860-7179",
publisher = "John Wiley and Sons Ltd",

}

TY - JOUR

T1 - Unconventional Coupling between Ligand Recognition and Allosteric Control in the Multidrug Resistance Gene Regulator, BmrR

AU - Bachas, Sharrol

AU - Kohrs, Bryan

AU - Wade, Herschel

PY - 2017

Y1 - 2017

N2 - 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 invitro 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 L50, RMAX and N. We found that L50 values correlate directly with ΔGBIND values, suggesting that the parameter reflects binding, whereas RMAX 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.

AB - 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 invitro 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 L50, RMAX and N. We found that L50 values correlate directly with ΔGBIND values, suggesting that the parameter reflects binding, whereas RMAX 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.

KW - Allosterism

KW - Biosensors

KW - In vitro transcription

KW - Molecular recognition

KW - Multidrug resistance

UR - http://www.scopus.com/inward/record.url?scp=85013135347&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85013135347&partnerID=8YFLogxK

U2 - 10.1002/cmdc.201700017

DO - 10.1002/cmdc.201700017

M3 - Article

JO - ChemMedChem

JF - ChemMedChem

SN - 1860-7179

ER -