We have identified two basic residues that are important for the recognition of secretin and vasoactive intestinal peptide (VIP) by their respective receptors. These two peptides containing an Asp residue at position 3 interacted with an arginine residue in transmembrane helix 2 (TM2) of the receptor, and the lysine residue in extracellular loop 1 (ECL1) stabilized the active receptor conformation induced by the ligand. The glucagon receptor possesses a Lys instead of an Arg in TM2, and an Ile instead of Lys in ECL1; it markedly prefers a Gln side chain in position 3 of the ligand. Our results suggested that, in the wild-type receptor, the Ile side chain prevented access to the TM2 Lys side chain, but oriented the glucagon Gln3 side chain to its proper binding site. In the double mutant, the ECL1 Lys allowed an interaction between negatively charged residues in position 3 of glucagon and the TM2 Arg, resulting in efficient receptor activation by [Asp3]glucagon as well as by glucagon.
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August 2002
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Conference Article|
August 01 2002
Identification of secretin, vasoactive intestinal peptide and glucagon binding sites: from chimaeric receptors to point mutations
M. Waelbroeck;
M. Waelbroeck
1
1Department of Biochemistry and Nutrition, School of Medicine, Université Libre de Bruxelles, Bât G/E, CP 611, 808 route de Lennik, B-1070 Brussels, Belgium
1To whom correspondence should be addressed (e-mail [email protected])
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J. Perret;
J. Perret
1Department of Biochemistry and Nutrition, School of Medicine, Université Libre de Bruxelles, Bât G/E, CP 611, 808 route de Lennik, B-1070 Brussels, Belgium
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P. Vertongen;
P. Vertongen
1Department of Biochemistry and Nutrition, School of Medicine, Université Libre de Bruxelles, Bât G/E, CP 611, 808 route de Lennik, B-1070 Brussels, Belgium
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M. Van Craenenbroeck;
M. Van Craenenbroeck
1Department of Biochemistry and Nutrition, School of Medicine, Université Libre de Bruxelles, Bât G/E, CP 611, 808 route de Lennik, B-1070 Brussels, Belgium
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P. Robberecht
P. Robberecht
1Department of Biochemistry and Nutrition, School of Medicine, Université Libre de Bruxelles, Bât G/E, CP 611, 808 route de Lennik, B-1070 Brussels, Belgium
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Publisher: Portland Press Ltd
Received:
March 13 2002
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2002 Biochemical Society
2002
Biochem Soc Trans (2002) 30 (4): 437–441.
Article history
Received:
March 13 2002
Citation
M. Waelbroeck, J. Perret, P. Vertongen, M. Van Craenenbroeck, P. Robberecht; Identification of secretin, vasoactive intestinal peptide and glucagon binding sites: from chimaeric receptors to point mutations. Biochem Soc Trans 1 August 2002; 30 (4): 437–441. doi: https://doi.org/10.1042/bst0300437
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