Positively charged residues at positions 12, 17, and 18 of glucagon ensure maximum biological potency.

The Journal of Biological Chemistry
C G UnsonR B Merrifield

Abstract

Glucagon is a peptide hormone that plays a central role in the maintenance of normal circulating glucose levels. Structure-activity studies have previously demonstrated the importance of histidine at position 1 and the absolute requirement for aspartic acid at position 9 for transduction of the hormonal signal. Site-directed mutagenesis of the receptor protein identified Asp64 on the extracellular N-terminal tail to be crucial for the recognition function of the receptor. In addition, antibodies generated against aspartic acid-rich epitopes from the extracellular region competed effectively with glucagon for receptor sites, which suggested that negative charges may line the putative glucagon binding pocket in the receptor. These observations led to the idea that positively charged residues on the hormone may act as counterions to these sites. Based on these initial findings, we synthesized glucagon analogs in which basic residues at positions 12, 17, and 18 were replaced with neutral or acidic residues to examine the effect of altering the positive charge on those sites on binding and adenylyl cyclase activity. The results indicate that unlike N-terminal histidine, Lys12, Arg17, and Arg18 of glucagon have very large effects on ...Continue Reading

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Citations

Dec 20, 2002·Biopolymers·Cecilia G Unson
Aug 30, 2008·Science in China. Series C, Life Sciences·C WenS Zhu
Sep 1, 2005·Canadian Journal of Applied Physiology = Revue Canadienne De Physiologie Appliquée·Carole Lavoie
Jul 21, 2016·AAPS PharmSciTech·Jian Zhang
Dec 12, 2013·Molecular Metabolism·Brian P WardRichard D Dimarchi
Nov 28, 2019·Journal of Medicinal Chemistry·Joseph ChabenneRichard D DiMarchi
May 5, 2000·Journal of Medicinal Chemistry·D TrivediV J Hruby

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