Reversible and specific extracellular antagonism of receptor-histidine kinase signaling
Gholson J Lyon1, Jesse S Wright, Arthur Christopoulos
1Laboratory of Synthetic Protein Chemistry, The Rockefeller University, New York, New York 10021, USA.
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.
Related Concept Videos
Amplifying Signals via Enzymatic Cascade
GPCR Desensitization
The JAK-STAT Signaling Pathway
Transducer Mechanism: Enzyme-Linked Receptors
Major types that are helpful drug targets include:
Receptor Tyrosine Kinases
Receptor Downregulation in MVBs
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR activation may...


