Glucagon-like peptides (GLP-1 and GLP-2) are two proglucagon-derived intestinal hormones that mediate distinct physiological functions through two related receptors (GLP-1R and GLP-2R) which are important drug targets for metabolic disorders and Crohn’s disease, respectively. Despite great progress in GLP-1R structure determination, our understanding on the differences of peptide binding and signal transduction between these two receptors remains elusive. Here we report the electron microscopy structure of the human GLP-2R in complex with GLP-2 and a G_s heterotrimer. To accommodate GLP-2 rather than GLP-1, GLP-2R fine-tunes the conformations of the extracellular parts of transmembrane helices (TMs) 1, 5, 7 and extracellular loop 1 (ECL1). In contrast to GLP-1, the N-terminal histidine of GLP-2 penetrates into the receptor core with a unique orientation. The middle region of GLP-2 engages with TM1 and TM7 more extensively than with ECL2, and the GLP-2 C-terminus closely attaches to ECL1, which is the most protruded among 9 class B G protein-coupled receptors (GPCRs). Functional studies revealed that the above three segments of GLP-2 are essential for GLP-2 recognition and receptor activation, especially the middle region. These results provide new insights into the molecular basis of ligand specificity in class B GPCRs and may facilitate the development of more specific therapeutics.

胰高血糖素样肽（GLP-1 和 GLP-2）是两种胰高血糖素原衍生的肠道激素，它们通过两个相关受体（GLP-1R 和 GLP-2R）介导不同的生理功能，这些受体是代谢紊乱和克罗恩病的重要药物靶点，分别。尽管 GLP-1R 结构测定取得了很大进展，但我们对这两种受体之间肽结合和信号转导的差异的理解仍然难以捉摸。在这里，我们用GLP-2和克报告人GLP-2R的电子显微结构在复杂的_小号异源三聚体。为了适应 GLP-2 而不是 GLP-1，GLP-2R 微调跨膜螺旋 (TM) 1、5、7 和细胞外环 1 (ECL1) 的细胞外部分的构象。与 GLP-1 不同，GLP-2 的 N 端组氨酸以独特的方向渗透到受体核心中。GLP-2 的中间区域与 TM1 和 TM7 的结合比与 ECL2 更广泛，GLP-2 C 端与 ECL1 紧密相连，这是 9 类 BG 蛋白偶联受体 (GPCR) 中最突出的。功能研究表明，GLP-2的上述三个片段对于GLP-2识别和受体激活是必不可少的，尤其是中间区域。这些结果为 B 类 GPCR 中配体特异性的分子基础提供了新的见解，并可能促进更具体的治疗方法的开发。