title: Reversible and specific extracellular antagonism of receptor-histidine kinase signaling.
abstract: Staphylococcal pathogenesis is regulated by a two-component quorum-sensing system, agr, activated by a self-coded autoinducing peptide (AIP). The agr system is widely divergent and is unique in that variant AIPs cross-inhibit agr activation in heterologous combinations. Cross-inhibition, but not self-activation, is widely tolerant of structural diversity in the AIPs so that these two processes must involve different mechanisms of interaction with the respective receptors. Herein, we have utilized this naturally occurring antagonism to demonstrate that both activation and inhibition are reversible and that activators and inhibitors interact at a common site on the receptor. These results suggest that molecules designed to compete with natural agonists for binding at receptor-histidine kinase sensor domains could represent a general approach to the inhibition of receptor-histidine kinase signaling.
authors.affiliation: Laboratory of Synthetic Protein Chemistry, The Rockefeller University, New York, New York 10021, USA.
authors.forename: Gholson J
authors.initials: GJ
authors.lastname: Lyon
authors.forename: Jesse S
authors.initials: JS
authors.lastname: Wright
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
authors.forename: Richard P
authors.initials: RP
authors.lastname: Novick
authors.forename: Tom W
authors.initials: TW
authors.lastname: Muir
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D014644:Genetic Variation; D000071677:Histidine Kinase; D007700:Kinetics; D010456:Peptides, Cyclic; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013211:Staphylococcus aureus / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism
chemical_list: C095698:Agr protein, Staphylococcus aureus; C414532:AgrD protein, Staphylococcus; D001426:Bacterial Proteins; D010456:Peptides, Cyclic; D047428:Protein Kinase Inhibitors; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D011494:Protein Kinases; D000071677:Histidine Kinase