Premium
Mechanism of Action and Structural Requirements of Constrained Peptide Inhibitors of RGS Proteins
Author(s) -
Roof Rebecca A.,
Jin Yafei,
Roman David L.,
Sunahara Roger K.,
Ishii Masaru,
Mosberg Henry I.,
Neubig Richard R.
Publication year - 2006
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2006.00373.x
Subject(s) - peptide , chemistry , mechanism of action , microbiology and biotechnology , biochemistry , g protein , receptor , allosteric regulation , rgs2 , biology , gtpase activating protein , in vitro
Regulators of G‐protein signaling (RGS) accelerate guanine triphosphate hydrolysis by G α ‐subunits and profoundly inhibit signaling by G protein‐coupled receptors. The distinct expression patterns and pathophysiologic regulation of RGS proteins suggest that inhibitors may have therapeutic potential. We previously reported the design of a constrained peptide inhibitor of RGS4 ( 1 : Ac ‐Val‐Lys‐[Cys‐Thr‐Gly‐Ile‐Cys]‐Glu‐ NH 2 , S‐S) based on the structure of the Gαi switch 1 region but its mechanism of action was not established. In the present study, we show that 1 inhibits RGS4 by mimicking and competing for binding with the switch 1 region of Gαi and that peptide 1 shows selectivity for RGS4 and RGS8 versus RGS7. Structure–activity relationships of analogs related to 1 are described that illustrate key features for RGS inhibition. Finally, we demonstrate activity of the methylene dithioether‐bridged peptide inhibitor, 2, to modulate muscarinic receptor‐regulated potassium currents in atrial myocytes. These data support the proposed mechanism of action of peptide RGS inhibitors, demonstrate their action in native cells, and provide a starting point for the design of RGS inhibitor drugs.