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 rec eptor has been evidenced. The mutation of Ser(105) into alanine comple tely abolished peptide agonist and antagonist binding, while the bindi ng of nonpeptide ligands, including the original radioligands [H-3] LF 7-0156 and [H-3] LF 8-0129, was more moderately affected. Reverse pha rmacological changes, i.e., unchanged affinities for peptide agonists or antagonists and drastically reduced affinities for nonpeptide antag onists,were observed upon alanine replacement of Asn(111). These resul ts confirm that the binding sites for peptide and nonpeptide molecules are not totally overlapping and delineate new amino acids as candidat es for the selective receptor interaction with the two categories of l igands. Their integration in topographical studies is discussed. (C) 1 995 Academic Press, Inc.