Department of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, Wisconsin, 53706, USA.
Chembiochem. 2023 Nov 2;24(21):e202300504. doi: 10.1002/cbic.202300504. Epub 2023 Sep 13.
Agonists of the glucagon-like peptide-1 receptor (GLP-1R) are used to treat diabetes and obesity. Cryo-EM structures indicate that GLP-1 is completely α-helical when bound to the GLP-1R. The mature form of this hormone, GLP-1(7-36), contains a glycine residue near the center (Gly22). Since glycine has the second-lowest α-helix propensity among the proteinogenic α-amino acid residues, and Gly22 does not appear to make direct contact with the receptor, we were motivated to explore the impact on agonist activity of altering the α-helix propensity at this position. We examined GLP-1 analogues in which Gly22 was replaced with L-Ala, D-Ala, or β-amino acid residues with varying helix propensities. The results suggest that the receptor is reasonably tolerant of variations in helix propensity, and that the functional receptor-agonist complex may comprise a conformational spectrum rather than a single fixed structure.
胰高血糖素样肽-1 受体 (GLP-1R) 的激动剂被用于治疗糖尿病和肥胖症。冷冻电镜结构表明，GLP-1 与 GLP-1R 结合时完全呈 α-螺旋构象。这种激素的成熟形式，GLP-1(7-36)，在靠近中心的位置（Gly22）含有一个甘氨酸残基。由于甘氨酸是蛋白质α-氨基酸残基中 α-螺旋倾向第二低的氨基酸，并且 Gly22 似乎不与受体直接接触，因此我们有动机探索改变该位置的 α-螺旋倾向对激动剂活性的影响。我们研究了 GLP-1 类似物，其中 Gly22 被 L-Ala、D-Ala 或具有不同螺旋倾向的β-氨基酸残基取代。结果表明，受体对螺旋倾向的变化具有相当的耐受性，并且功能性受体-激动剂复合物可能包含构象谱而不是单一的固定结构。
