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J. Biol. Chem., Vol. 277, Issue 8, 6247-6253, February 22, 2002
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From the 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.
Reversible and Specific Extracellular Antagonism of
Receptor-Histidine Kinase Signaling*
§§,
,
Laboratory of Synthetic Protein Chemistry,
The Rockefeller University, New York, New York 10021, the
§ Molecular Pathogenesis Program, Skirball Institute of
Biomolecular Medicine, New York University Medical Center, New York,
New York 10016, and the ¶ Department of Pharmacology, University
of Melbourne, Parkville, Victoria 3010, Australia
*
This work was supported by the Burroughs-Wellcome
Fund (to T. W. M.), and NIH Grant AI 42783 (to R. P. N.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
C. R. Roper Research Fellow of the Faculty of Medicine,
Dentistry, and Health Sciences at the University of Melbourne.
**
To whom correspondence may be addressed: Molecular Pathogenesis
Program and Departments of Microbiology and Medicine, Skirball Institute of Biomolecular Medicine, New York University School of
Medicine, 540 First Ave., New York, NY 10016. Tel.: 212-263-6290; Fax:
212-263-5711; E-mail: novick@saturn.med.nyu.edu.
To whom correspondence may be addressed: Laboratory of
Synthetic Protein Chemistry, The Rockefeller University, 1230 York Ave., New York, NY 10021. Tel.: 212-327-7368; Fax: 212-327-7358; E-mail: muirt@mail.rockefeller.edu.
§§
Supported by Medical Scientist Training Program Grant GM07739.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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