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Unconventional surface plasmon resonance signals reveal quantitative inhibition of transcriptional repressor EthR by synthetic ligands.

Abstract
EthR is a mycobacterial repressor that limits the bioactivation of ethionamide, a commonly used anti-tuberculosis second-line drug. Several efforts have been deployed to identify EthR inhibitors abolishing the DNA-binding activity of the repressor. This led to the demonstration that stimulating the bioactivation of Eth through EthR inhibition could be an alternative way to fight Mycobacterium tuberculosis. We propose a new surface plasmon resonance (SPR) methodology to study the affinity between inhibitors and EthR. Interestingly, the binding between inhibitors and immobilized EthR produced a dose-dependent negative SPR signal. We demonstrate that this signal reveals the affinity of small molecules for the repressor. The affinity constants (K(D)) correlate with their capacity to inhibit the binding of EthR to DNA. We hypothesize that conformational changes in EthR during ligand interaction could be responsible for this SPR signal. Practically, this unconventional result opens perspectives onto the development of an SPR assay that would at the same time reveal structural changes in the target upon binding with an inhibitor and the binding constant of this interaction.
AuthorsCéline Crauste, Nicolas Willand, Baptiste Villemagne, Marion Flipo, Eve Willery, Xavier Carette, Martin Moune Dimala, Anne-Sophie Drucbert, Pierre-Marie Danze, Benoit Deprez, Alain R Baulard
JournalAnalytical biochemistry (Anal Biochem) Vol. 452 Pg. 54-66 (May 01 2014) ISSN: 1096-0309 [Electronic] United States
PMID24561027 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier Inc. All rights reserved.
Chemical References
  • EthR protein, Mycobacterium tuberculosis
  • Ligands
  • Repressor Proteins
Topics
  • Biotinylation
  • Ligands
  • Mycobacterium tuberculosis
  • Repressor Proteins (antagonists & inhibitors, chemistry, metabolism)
  • Surface Plasmon Resonance (methods)
  • Transition Temperature

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