An Autoinducer Analogue Reveals an Alternative Mode of Ligand Binding for the LasR Quorum-Sensing Receptor.

TitleAn Autoinducer Analogue Reveals an Alternative Mode of Ligand Binding for the LasR Quorum-Sensing Receptor.
Publication TypeJournal Article
Year of Publication2019
AuthorsPaczkowski, JE, McCready, AR, Cong, J-P, Li, Z, Jeffrey, PD, Smith, CD, Henke, BR, Hughson, FM, Bassler, BL
JournalACS Chem Biol
Date Published2019 Mar 15
Keywords4-Butyrolactone, Amino Acids, Bacterial Proteins, Escherichia coli, Ligands, Molecular Structure, Mutation, Protein Binding, Pseudomonas aeruginosa, Quorum Sensing, Signal Transduction, Structure-Activity Relationship, Trans-Activators

<p>Bacteria use a cell-cell communication process called quorum sensing to coordinate collective behaviors. Quorum sensing relies on production and group-wide detection of extracellular signal molecules called autoinducers. Here, we probe the activity of the Pseudomonas aeruginosa LasR quorum-sensing receptor using synthetic agonists based on the structure of the native homoserine lactone autoinducer. The synthetic compounds range from low to high potency, and agonist activity tracks with the ability of the agonist to stabilize the LasR protein. Structural analyses of the LasR ligand binding domain complexed with representative synthetic agonists reveal two modes of ligand binding, one mimicking the canonical autoinducer binding arrangement, and the other with the lactone head group rotated approximately 150°. Iterative mutagenesis combined with chemical synthesis reveals the amino acid residues and the chemical moieties, respectively, that are key to enabling each mode of binding. Simultaneous alteration of LasR residues Thr75, Tyr93, and Ala127 converts low-potency compounds into high-potency compounds and converts ligands that are nearly inactive into low-potency compounds. These results show that the LasR binding pocket displays significant flexibility in accommodating different ligands. The ability of LasR to bind ligands in different conformations, and in so doing, alter their potency as agonists, could explain the difficulties that have been encountered in the development of competitive LasR inhibitors.</p>

Alternate JournalACS Chem Biol
PubMed ID30763066
PubMed Central IDPMC6601336
Grant ListR01 GM065859 / GM / NIGMS NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States
R37 GM065859 / GM / NIGMS NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
R56 AI091681 / AI / NIAID NIH HHS / United States
P30 EB009998 / EB / NIBIB NIH HHS / United States