Journal
MOLECULAR CELL
Volume 42, Issue 2, Pages 199-209Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2011.04.003
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Funding
- Howard Hughes Medical Institute (HHMI)
- NIH [AI054442, GM065859]
- National Science Foundation [MCB-0343821]
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Quorum-sensing bacteria communicate via small molecules called autoinducers to coordinate collective behaviors. Because quorum sensing controls virulence factor expression in many clinically relevant pathogens, membrane-permeable quorum sensing antagonists that prevent population-wide expression of virulence genes offer a potential route to novel antibacterial therapeutics. Here, we report a strategy for inhibiting quorum-sensing receptors of the widespread LuxR family. Structure-function studies with natural and synthetic ligands demonstrate that the dimeric LuxR-type transcription factor CviR from Chromobacterium violaceum is potently antagonized by molecules that bind in place of the native acylated homoserine lactone autoinducer, provided that they stabilize a closed conformation. In such conformations, each of the two DNA-binding domains interacts with the ligand-binding domain of the opposing monomer. Consequently, the DNA-binding helices are held apart by similar to 60 angstrom, twice the similar to 30 angstrom separation required for operator binding. This approach may represent a general strategy for the inhibition of multidomain proteins.
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