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Mechanism of agonism and antagonism of the Pseudomonas aeruginosa quorum sensing regulator QscR with non‐native ligands

Year: 2018
Type: article
Abstract: Pseudomonas aeruginosa is an opportunistic pathogen that uses the process of quorum sensing (QS) to coordinate the expression of many virulence genes. During quorum sensing, N-acyl-homoserine lactone (AHL) signaling molecules regulate the activity of three LuxR-type transcription factors, LasR, RhlR and QscR. To better understand P. aeruginosa QS signal reception, we examined the mechanism underlying the response of QscR to synthetic agonists and antagonists using biophysical and structural approaches. The structure of QscR bound to a synthetic agonist reveals a novel mode of ligand binding supporting a general mechanism for agonist activity. In turn, antagonists of QscR with partial agonist activity were found to destabilize and greatly impair QscR dimerization and DNA binding. These results highlight the diversity of LuxR-type receptor responses to small molecule agonists and antagonists and demonstrate the potential for chemical strategies for the selective targeting of individual QS systems.
DOI: 10.1111/mmi.13930
Authors: Christina L. Wysoczynski‐Horita, Michelle E. Boursier, Ryan Hill, Kirk Hansen, Helen E. Blackwell, Mair E. A. Churchill
Language: English
Open Access status: green
Funders: Burroughs Wellcome Fund, National Institutes of Health, University of Colorado Denver, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Center for Advancing Translational Sciences
Awards: G1465144010, G172409220, Macromolecular X-ray Data Collection Instrumentation, Quantum 315 r Detector, Colorado Clinical and Translational Sciences Institute, G9000074531, University of Colorado Cancer Center Support Grant, G9001225491
OpenAlex ID: W2790465394
FWCI: 1.69
Cites: 66
Cited by: 52
Related to: 10