Site-directed mutagenesis of the histamine H1-receptor reveals a selective interaction of asparagine207 with subclasses of H1-receptor agonists.
In this study we investigated the role of the threonine203 and the asparagine207 residues in the fifth transmembrane domain of the guinea-pig histamine H1-receptor by site-directed mutagenesis to non-functional alanines. Whereas the threonine203 residue is not important for the action of histamine, the asparagine207 residue appears to be involved in the binding of the N tau-nitrogen atom of histamine and its 2-methyl-analogue. For the 2-phenyl-analogue and non-imidazole H1-receptor agonists, this residue is, however, not essential for binding. On the basis of this study we conclude that different histamine H1-receptor agonists interact in different ways with the H1-receptor protein. Moreover, we speculate that the interaction with the N pi-nitrogen atom is essential for H1-receptor activation.
Leurs
R
R
Leiden/Amsterdam Center for Drug Research, Department of Pharmacochemistry, The Netherlands.
Smit
M J
MJ
Tensen
C P
CP
Ter Laak
A M
AM
Timmerman
H
H
D000818:Animals; D001216:Asparagine / Q000737:chemistry; D001483:Base Sequence; D002744:Chlorpheniramine / Q000737:chemistry; D017931:DNA Primers / Q000737:chemistry; D006168:Guinea Pigs; D006632:Histamine / Q000737:chemistry; D017442:Histamine Agonists / Q000737:chemistry*; D007295:Inositol Phosphates / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011738:Pyrilamine / Q000737:chemistry; D011969:Receptors, Histamine H1 / Q000737:chemistry*; D013329:Structure-Activity Relationship
D017931:DNA Primers; D017442:Histamine Agonists; D007295:Inositol Phosphates; D011969:Receptors, Histamine H1; D002744:Chlorpheniramine; D001216:Asparagine; D006632:Histamine; D011738:Pyrilamine