Eunice Murage - Search for alpha-helical propensity in the receptor-bound conformation of glucagon-like peptide-1

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  Publication Details (including relevant citation   information):

    Eunice Murage, Jonathan C. Schroeder, Martin Beinborn,   Jung-Mo Ahn

    Bioorganic & Medicinal Chemistry,   2008, 16, 23, 10106-10112.


  To elucidate the receptor-bound conformation of glucagon-like   peptide-1 (GLP-1), a series of conformationally constrained GLP-1   analogues were synthesized by introducing lactam bridges between   Lys-i and Glu-i+4 to form alpha-helices at various positions. The   activity and affinity of these analogues to GLP-1 receptors   suggested that the receptor-bound conformation comprises two   alpha-helical segments between residues 1-21 and 23-34. It is   notable that the N-terminal alpha-helix is extended to Thr11, and   that Gly22 plays a pivotal role in arranging the two   alpha-helices. Based on these findings, a highly potent bicyclic   GLP-1 analogue was synthesized which is the most conformationally   constrained GLP-1 analogue reported to date

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