Structural and Biochemical Studies of Non-native Agonists of the LasR Quorum-Sensing Receptor Reveal an L3 Loop "Out" Conformation for LasR

Cell Chemical Biology
Matthew C O'ReillyHelen E Blackwell

Abstract

Chemical strategies to block quorum sensing (QS) could provide a route to attenuate virulence in bacterial pathogens. Considerable research has focused on this approach in Pseudomonas aeruginosa, which uses the LuxR-type receptor LasR to regulate much of its QS network. Non-native ligands that antagonize LasR have been developed, yet we have little understanding of the mode by which these compounds interact with LasR and alter its function, as the receptor is unstable in their presence. Herein, we report an approach to circumvent this challenge through the study of a series of synthetic LasR agonists with varying levels of potency. Structural investigations of these ligands with the LasR ligand-binding domain reveal that certain agonists can enforce a conformation that deviates from that observed for other, often more potent agonists. These results, when combined with cell-based and biophysical analyses, suggest a functional model for LasR that could guide future ligand design.

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Citations

Nov 10, 2018·Beilstein Journal of Organic Chemistry·Matthew J Styles, Helen E Blackwell
Mar 11, 2019·Applied Microbiology and Biotechnology·Syed A K S AhmedIbrahim M Banat
Aug 23, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Suhaib SadiqAbdul Rauf Siddiqi
Dec 19, 2018·Proceedings of the National Academy of Sciences of the United States of America·Amelia R McCreadyBonnie L Bassler
Jan 20, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Mariana Paola Espinosa-ValdésMarco A Loza-Mejía
May 21, 2019·Frontiers in Microbiology·B X V QuecanU M Pinto
Nov 27, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Victor MarkusKarina Golberg
Apr 4, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Victor MarkusAriel Kushmaro

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