Structural and Biochemical Studies of Non-native Agonists of the LasR Quorum-Sensing Receptor Reveal an L3 Loop "Out" Conformation for LasR. Issue 9 (20th September 2018)

• Record Type: Journal Article
• Authors: O'Reilly, Matthew C.; Dong, Shi-Hui; Rossi, Francis M.; Karlen, Kaleigh M.; Kumar, Rohan S.; Nair, Satish K.; Blackwell, Helen E.
• Is Part Of: Cell chemical biology. Volume 25:Issue 9(2018)
• Page Start: 1128
• Page End: 1139.e3
• Publication Date: 2018-09-20
• Subjects: quorum sensing -- Pseudomonas aeruginosa -- LuxR-type receptor -- autoinduction -- cell-cell signaling -- synthetic ligand -- LasR -- transcription factor -- protein structure -- bacteria; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2018.06.007
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical Abstract: Highlights: A set of triphenyl derivatives was found to activate LasR with varied potencies Ligand potency correlated with thermal stabilization of the LasR ligand-binding domain Certain agonists altered the conformation of a loop in LasR ligand-binding domain A model is proposed for modulation of LasR activity by synthetic ligands Abstract : O'Reilly et al. describe characterization of the LasR quorum-sensing receptor in P. aeruginosa with a series of synthetic agonists of different potencies and propose a mechanism by which this LuxR-type receptor recognizes and is activated by synthetic ligands.