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PLoS Biol. 2016 May 24;14(5):e1002464. doi: 10.1371/journal.pbio.1002464. eCollection 2016 May.

Structure, Regulation, and Inhibition of the Quorum-Sensing Signal Integrator LuxO.

Author information

1
Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America.
2
Department of Biology, Haverford College, Haverford, Pennsylvania, United States of America.
3
Department of Chemistry, Princeton University, Princeton, New Jersey, United States of America.
4
Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America.

Abstract

In a process called quorum sensing, bacteria communicate with chemical signal molecules called autoinducers to control collective behaviors. In pathogenic vibrios, including Vibrio cholerae, the accumulation of autoinducers triggers repression of genes responsible for virulence factor production and biofilm formation. The vibrio autoinducer molecules bind to transmembrane receptors of the two-component histidine sensor kinase family. Autoinducer binding inactivates the receptors' kinase activities, leading to dephosphorylation and inhibition of the downstream response regulator LuxO. Here, we report the X-ray structure of LuxO in its unphosphorylated, autoinhibited state. Our structure reveals that LuxO, a bacterial enhancer-binding protein of the AAA+ ATPase superfamily, is inhibited by an unprecedented mechanism in which a linker that connects the catalytic and regulatory receiver domains occupies the ATPase active site. The conformational change that accompanies receiver domain phosphorylation likely disrupts this interaction, providing a mechanistic rationale for LuxO activation. We also determined the crystal structure of the LuxO catalytic domain bound to a broad-spectrum inhibitor. The inhibitor binds in the ATPase active site and recapitulates elements of the natural regulatory mechanism. Remarkably, a single inhibitor molecule may be capable of inhibiting an entire LuxO oligomer.

PMID:
27219477
PMCID:
PMC4878744
DOI:
10.1371/journal.pbio.1002464
[Indexed for MEDLINE]
Free PMC Article

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