AMINO-ACIDS OF THE 3RD TRANSMEMBRANE DOMAIN OF THE AT(1A) ANGIOTENSIN-II RECEPTOR ARE INVOLVED IN THE DIFFERENTIAL RECOGNITION OF PEPTIDE AND NONPEPTIDE LIGANDS

The differential role of amino acids of the third transmembrane domain on peptide and nonpeptide recognition by the AT(1) angiotensin II receptor has been evidenced. The mutation of Ser(105) into alanine completely abolished peptide agonist and antagonist binding, while the binding of nonpeptide ligands, including the original radioligands [H-3] LF 7-0156 and [H-3] LF 8-0129, was more moderately affected. Reverse pharmacological changes, i.e., unchanged affinities for peptide agonists or antagonists and drastically reduced affinities for nonpeptide antagonists,were observed upon alanine replacement of Asn(111). These results confirm that the binding sites for peptide and nonpeptide molecules are not totally overlapping and delineate new amino acids as candidates for the selective receptor interaction with the two categories of ligands. Their integration in topographical studies is discussed. (C) 1995 Academic Press, Inc.