SITE-DIRECTED MUTAGENESIS OF THE HISTAMINE H-1 RECEPTOR - ROLES OF ASPARTIC ACID(107), ASPARAGINE(198) AND THREONINE(194)

Based on structural comparison with other biogenic amine receptors and the histamine H-2 receptor, it has been suggested that in the human histamine H-1 receptor, Asp(107), Thr(194), and Asn(198) are the residues involved in binding of histamine. We therefore used site-directed mutagenesis to investigate the roles of these three amino acid residues. Asp(107) was essential for both agonist and antagonist binding. Asn(198) was necessary for agonist but not for antagonist binding. Thr(194) was not important for either type of binding. A good correlation was found between agonist binding and receptor activation for ail the wild-type and mutant receptors. The results show that the histamine H-1 receptor recognizes and is activated by histamine through the interactions of Asp(107) and the amino group, and Asn(198) and the imidazole ring. (C) 1994 Academic Press, Inc.