TY - JOUR
T1 - Reversible and specific extracellular antagonism of receptor-histidine kinase signaling
AU - Lyon, Gholson J.
AU - Wright, Jesse S.
AU - Christopoulos, Arthur
AU - Novick, Richard P.
AU - Muir, Tom W.
PY - 2002/2/22
Y1 - 2002/2/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0037155217&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037155217&partnerID=8YFLogxK
U2 - 10.1074/jbc.M109989200
DO - 10.1074/jbc.M109989200
M3 - Article
C2 - 11733525
AN - SCOPUS:0037155217
SN - 0021-9258
VL - 277
SP - 6247
EP - 6253
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 8
ER -