The role of histidine-1 in glucagon action.
The identification of position 9 aspartic acid in glucagon as a critical residue for transduction reinforced the notion that specific residues in the peptide sequence dictate either receptor recognition or biological activity. It was evident from our studies that Asp9 operates in conjunction with His1 as part of the activation mechanism that follows binding to the glucagon receptor. This investigation was conducted to delineate structural features of histidine that contribute to its role in glucagon action. We report, based on binding and activity data from 10 replacement analogs, that the imidazole ring of His1 furnishes an aromatic determinant for receptor binding affinity and that its protonatable imidazole nitrogen is important for transduction.
Rockefeller University, New York, New York 10021.
C G
CG
Unson
D
D
Macdonald
R B
RB
Merrifield
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D002462:Cell Membrane; D000242:Cyclic AMP / Q000378:metabolism; D005934:Glucagon / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D006639:Histidine / Q000031:analogs & derivatives*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011964:Receptors, Gastrointestinal Hormone / Q000378:metabolism*; D018027:Receptors, Glucagon; D013329:Structure-Activity Relationship
D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; D006639:Histidine; D005934:Glucagon; D000242:Cyclic AMP; D000262:Adenylyl Cyclases