The glucagon-like peptide (GLP)-1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) that mediates the action of GLP-1, a peptide hormone secreted from three major tissues in humans, enteroendocrine L cells in the distal intestine, α cells in the pancreas, and the central nervous system, which exerts important actions useful in the management of type 2 diabetes mellitus and obesity, including glucose homeostasis and regulation of gastric motility and food intake. Peptidic analogs of GLP-1 have been successfully developed with enhanced bioavailability and pharmacological activity. Physiologic and biochemical studies with truncated, chimeric, and mutated peptides and GLP-1R variants, together with ligand-bound crystal structures of the extracellular domain and the first three-dimensional structures of the 7-helical transmembrane domain of class B GPCRs, have provided the basis for a two-domain-binding mechanism of GLP-1 with its cognate receptor. Although efforts in discovering therapeutically viable nonpeptidic GLP-1R agonists have been hampered, small-molecule modulators offer complementary chemical tools to peptide analogs to investigate ligand-directed biased cellular signaling of GLP-1R. The integrated pharmacological and structural information of different GLP-1 analogs and homologous receptors give new insights into the molecular determinants of GLP-1R ligand selectivity and functional activity, thereby providing novel opportunities in the design and development of more efficacious agents to treat metabolic disorders.

中文翻译：

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胰高血糖素样肽1及其类BG蛋白偶联受体：治疗成功的漫长征途。

胰高血糖素样肽（GLP）-1受体（GLP-1R）是BG类蛋白偶联受体（GPCR），它介导GLP-1的作用，GLP-1是从人体三个主要组织分泌的肠内分泌L细胞分泌的一种肽激素。在远端小肠中，胰腺和中枢神经系统中的α细胞发挥重要作用，可用于控制2型糖尿病和肥胖症，包括葡萄糖稳态以及胃动力和食物摄入的调节。已成功开发出具有增强的生物利用度和药理活性的GLP-1肽类似物。截短，嵌合和突变的肽和GLP-1R变体的生理生化研究，连同B类GPCR的胞外域的配体结合晶体结构和7螺旋跨膜结构域的第一个三维结构，为GLP-1及其同源受体的两结构域结合机制提供了基础。尽管发现治疗上可行的非肽GLP-1R激动剂的努力受到阻碍，但小分子调节剂为肽类似物提供了互补的化学工具，以研究GLP-1R的配体定向偏向细胞信号传导。不同的GLP-1类似物和同源受体的综合药理和结构信息为GLP-1R配体选择性和功能活性的分子决定因素提供了新见识，从而为设计和开发更有效的药物治疗代谢性疾病提供了新的机会。