MrtR of Mesorhizobium tianshanense reveals both activation and inhibition mechanisms of a LuxR-type quorum sensing receptor

Abstract

Quorum sensing (QS) enables common gram-negative bacteria to coordinate collective behaviors through small molecule signals, yet how these signals tune receptor activity remains incompletely understood. Here, we define a mechanism by which ligand structure controls function in a LuxR-type QS receptor. Using structural and biochemical analyses, we investigate MrtR from Mesorhizobium tianshanense and show that ligand acyl-chain length governs receptor assembly and activity. We present full-length structures of MrtR bound to activating and inhibitory ligands, revealing a switch in oligomeric state. Long-chain (C14) N-acyl L-homoserine lactones (AHLs) act as agonists by promoting intra- and inter-subunit interactions that lead to homodimerization and DNA binding. In contrast, shorter (C8) AHLs fail to promote these contacts, favoring a monomeric, inactive state. Ligands of intermediate length produce graded responses consistent with partial dimer stabilization. Biochemical measurements of DNA binding, thermostability, and oligomerization, together with targeted mutagenesis, support this model and establish the functional importance of key structural contacts. These findings provide the first structural comparison of a full-length LuxR-type receptor bound to both agonist and antagonist. Our findings expand the known structural and mechanistic diversity of the LuxR family and suggest mechanistic similarities between structurally distinct receptors. SIGNIFICANCEQuorum sensing (QS) regulates diverse bacterial behaviors, and LuxR-type receptors are attractive targets for applications ranging from antivirulence strategies to synthetic biology and agriculture. Despite intense interest in developing chemical modulators of these systems, the molecular basis by which small molecules agonize or antagonize LuxR-type receptors remains poorly understood. Here, we investigate the LuxR-type receptor MrtR and report crystal structures of the full-length receptor bound to an agonist and an antagonist, revealing how structurally similar compounds produce opposing outcomes. Notably, MrtR exhibits an unprecedented dimerization interface mediated by a ligand-responsive loop that undergoes large conformational changes. These findings establish a new structural framework for understanding signal discrimination in LuxR-type receptors and may enable rational reprogramming of QS in natural and engineered systems.