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Horm Metab Res 2012; 44(11): 804-809
DOI: 10.1055/s-0032-1321877
Original Basic
© Georg Thieme Verlag KG Stuttgart · New York

Identification of Key Residues for the Binding of Glucagon to the N-Terminal Domain of its Receptor: An Alanine Scan and Modeling Study

M. Prévost
1   Laboratoire de Structure et Fonction des Membranes Biologiques, Université Libre de Bruxelles, Brussels, Belgium
,
P. Vertongen
2   Biochemistry Department, Unité de Chimie Biologique et de la Nutrition, Université Libre de Bruxelles, Brussels, Belgium
,
M. Waelbroeck
2   Biochemistry Department, Unité de Chimie Biologique et de la Nutrition, Université Libre de Bruxelles, Brussels, Belgium
› Author Affiliations
Further Information

Publication History

received 14 December 2011

accepted 05 July 2012

Publication Date:
14 August 2012 (online)

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Abstract

Glucagon plays an essential role in the glycemia maintenance during fasting, but also aggravates hyperglycemia in diabetic patients. A series of analogues of glucagon were synthesized replacing each amino acid of the C-terminal region (residues 15–29) with alanine. The residues affecting the binding to the glucagon receptor are found to be located on one face of the glucagon helix. Several 3-dimensional models of the N-terminal domain of the glucagon receptor in complex with its ligand peptide were built and used to analyze the peptide-receptor interface in terms of the nature of the peptide residues and the interactions they form with the receptor. The models suggest that glucagon keeps its native helical structure upon binding, and that a large part of the interface formed with the receptor is hydrophobic. We find that in the C-terminal region, F22, V23, M27, and D15 are the most important residues for peptide binding. They bury a large portion of their solvent accessible surface area and make numerous interactions with the receptor mainly of the hydrophobic type.

Key words

class B receptor - ligand docking - receptor recognition - binding site
 

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