Ab initio study of aspartic and glutamic acid: Supplementary evidence for structural requirements at position 9 for glucagon activity

Anne Marie Sapse, Mihaly Mezei, Duli C. Jain, Cecille Unson

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Abstract

Our previous work established that position 9 aspartic acid in glucagon was a critical residue for transduction of the hormone response. An uncoupling of the binding interaction from adenylate cyclase activation was demonstrated by the observation that amino acid replacements at position 9 resulted in peptides that had no measurable adenylate cyclase activity yet were still recognized by the glucagon receptor. It was also later shown that His1 played a major role in activation, and it was suggested that an electrostatic interaction between the aspartic acid carboxylate and the histidine imidazole occurred as part of the activation mechanism. This did not preclude intermolecular interactions of this aspartic acid with other residues within the receptor binding site. The observation that a conservative substitution of glutamic acid for aspartic acid at position 9 was sufficient to result in the potent antagonist, des-His1d[Glu9]glucagon amide, implied that even glutamic acid possessed the minimum properties necessary for inhibition, and that the precise position of the carboxyl group at position 9 in glucagon was an absolute requirement for full agonist activity. The present investigation was conducted with ab initio calculations and molecular modeling to shed some light on the source of this phenomenon.

Original languageEnglish
Pages (from-to)225-233
Number of pages9
JournalJournal of Molecular Structure: THEOCHEM
Volume306
Issue number2-3
DOIs
StatePublished - 10 Apr 1994

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