GABA(B) receptor is a G protein-coupled receptor for GABA and drug target for neurological and psychiatric disorders. From the analysis of GTP gamma S binding assay, we found that a synthesized peptide (GABAb: ETKSVSTEKINDHR) corresponding to the intracellular third loop region of metabotropic GABAB receptor could activate G(i) protein alpha subunit directly. The three dimensional molecular structure of the peptide in SDS-d(25) micelles was determined by 2D H-1-NMR spectroscopy. GABAb peptide formed an a helical structure and a positive charge cluster at the C-terminal site. These structural features were also found in several other G protein activating peptides. From the comparison among these peptides, we found that peptides with high helical content show the high activity. (c) 2007 Elsevier Inc. All rights reserved.