Department of Chemistry, University of Southern California, California, Los Angeles.
Proteins. 2020 Jan;88(1):127-134. doi: 10.1002/prot.25777. Epub 2019 Aug 2.
G-protein-coupled receptors (GPCRs) are among the most important receptors in human physiology and pathology. They serve as master regulators of numerous key processes and are involved in as well as cause debilitating diseases. Consequently, GPCRs are among the most attractive targets for drug design and pharmaceutical interventions (>30% of drugs on the market). The glucagon-like peptide 1 (GLP-1) hormone receptor GLP1R is closely involved in insulin secretion by pancreatic β-cells and constitutes a major druggable target for the development of anti-diabetes and obesity agents. GLP1R structure was recently solved, with ligands, allosteric modulators and as part of a complex with its cognate G protein. However, the translation of this structural data into structure/function understanding remains limited. The current study functionally characterizes GLP1R with special emphasis on ligand and cellular partner binding interactions and presents a free-energy landscape as well as a functional model of the activation cycle of GLP1R. Our results should facilitate a deeper understanding of the molecular mechanism underlying GLP1R activation, forming a basis for improved development of targeted therapeutics for diabetes and related disorders.
G 蛋白偶联受体（GPCRs）是人类生理学和病理学中最重要的受体之一。它们作为许多关键过程的主要调节剂，参与并导致使人衰弱的疾病。因此，GPCR 是药物设计和药物干预的最有吸引力的目标之一（市场上 30%以上的药物）。胰高血糖素样肽 1（GLP-1）激素受体 GLP1R 与胰腺β细胞的胰岛素分泌密切相关，是开发抗糖尿病和肥胖药物的主要药物靶点。GLP1R 的结构最近已被解析，包括配体、别构调节剂以及与其同源 G 蛋白形成复合物的一部分。然而，将这些结构数据转化为结构/功能的理解仍然有限。本研究特别强调配体和细胞伴侣结合相互作用，对 GLP1R 的功能进行了表征，并提出了 GLP1R 激活循环的自由能景观和功能模型。我们的研究结果应该有助于更深入地了解 GLP1R 激活的分子机制，为开发针对糖尿病和相关疾病的靶向治疗药物提供基础。
