Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen 2200, Denmark; Section for Metabolic Receptology, Novo Nordisk Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark.
Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen 2200, Denmark.
Structure. 2021 Jul 1;29(7):679-693.e6. doi: 10.1016/j.str.2021.04.001. Epub 2021 Apr 22.
The glucose-dependent insulinotropic polypeptide (GIP) is a 42-residue metabolic hormone that is actively being targeted for its regulatory role of glycemia and energy balance. Limited structural data of its receptor has made ligand design tedious. This study investigates the structure and function of the GIP receptor (GIPR), using a homology model based on the GLP-1 receptor. Molecular dynamics combined with in vitro mutational data were used to pinpoint residues involved in ligand binding and/or receptor activation. Significant differences in binding mode were identified for the naturally occurring agonists GIP(1-30)NH and GIP(1-42) compared with high potency antagonists GIP(3-30)NH and GIP(5-30)NH. Residues R183, R190, and R300 are shown to be key for activation of the GIPR, and evidence suggests that a disruption of the K293-E362 salt bridge by GIPR antagonists strongly reduces GIPR activation. Combinatorial use of these findings can benefit rational design of ligands targeting the GIPR.
葡萄糖依赖性胰岛素多肽 (GIP) 是一种 42 个氨基酸残基的代谢激素，其血糖和能量平衡调节作用正受到广泛关注。由于其受体的结构数据有限，配体设计变得繁琐。本研究使用基于 GLP-1 受体的同源模型，研究 GIP 受体 (GIPR) 的结构和功能。将分子动力学与体外突变数据相结合，确定了参与配体结合和/或受体激活的残基。与高活性拮抗剂 GIP(3-30)NH 和 GIP(5-30)NH 相比，天然激动剂 GIP(1-30)NH 和 GIP(1-42)的结合模式存在显著差异。结果表明，R183、R190 和 R300 残基是 GIPR 激活的关键，并且有证据表明，GIPR 拮抗剂破坏 K293-E362 盐桥会强烈降低 GIPR 激活。这些发现的组合使用可以有助于针对 GIPR 的配体的合理设计。
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