Two distinct domains of the glucagon-like peptide-1 receptor control peptide-mediated biased agonism
Two distinct domains of the glucagon-like peptide-1 receptor control peptide-mediated biased agonism
复制标题
胰高血糖素样肽 1 受体的两个不同结构域控制肽介导的偏向激动。
DOI：
10.1074/jbc.ra118.003278
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发表时间：
2018-06-15
影响因子：
4.8
通讯作者：
Sexton, Patrick M.
中科院分区：
文献类型：
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作者：
Lei, Saifei;Clydesdale, Lachlan;Sexton, Patrick M.
G蛋白偶联受体（GPCRs）可被配体以不同方式激活，从而产生多种不同的下游信号传导模式，这一现象被称为偏向性激动作用。胰高血糖素样肽 - 1受体（GLP - 1R）属于B类GPCR，是治疗代谢紊乱的关键药物靶点；然而，其肽类激动剂表现出的偏向性信号传导会影响它们的相对疗效。在本研究中，我们将诱变实验与表面突变映射到最近描述的GLP - 1R结构上相结合，结果揭示了GLP - 1/GLP - 1R/G(s)蛋白活性结构中的两个主要结构域，它们对受体的静息状态以及偏向性激动作用的配体特异性起始和传播具有不同程度的重要性。跨膜螺旋（TM）5和TM 6构象的改变以及细胞外环2的重排，对于与环磷酸腺苷（cAMP）形成和细胞内钙动员相关的信号传导的传播至关重要，而TM1和TM7中氨基酸残基的排列和堆积则对细胞外信号调节激酶1/2（pERK）的活性至关重要。基于这些发现，我们提出了一个独特的肽 - 受体相互作用模型，该模型可选择性地控制这些不同信号通路的激活方式。这项工作为B类GPCR的激活和偏向性激动作用提供了重要的结构层面的见解。
G protein-coupled receptors (GPCRs) can be differentially activated by ligands to generate multiple and distinct downstream signaling profiles, a phenomenon termed biased agonism. The glucagon-like peptide-1 receptor (GLP-1R) is a class B GPCR and a key drug target for managing metabolic disorders; however, its peptide agonists display biased signaling that affects their relative efficacies. In this study, we combined mutagenesis experiments and mapping of surface mutations onto recently described GLP-1R structures, which revealed two major domains in the GLP-1/GLP-1R/G(s) protein active structure that are differentially important for both receptor quiescence and ligand-specific initiation and propagation of biased agonism. Changes to the conformation of transmembrane helix (TM) 5 and TM 6 and reordering of extracellular loop 2 were essential for the propagation of signaling linked to cAMP formation and intracellular calcium mobilization, whereas ordering and packing of residues in TMs 1 and 7 were critical for extracellular signal-regulated kinase 1/2 (pERK) activity. On the basis of these findings, we propose a model of distinct peptide-receptor interactions that selectively control how these different signaling pathways are engaged. This work provides important structural insight into class B GPCR activation and biased agonism.