Structural Determinants of Binding the Seven-transmembrane Domain of the Glucagon-like Peptide-1 Receptor (GLP-1R)
Structural Determinants of Binding the Seven-transmembrane Domain of the Glucagon-like Peptide-1 Receptor (GLP-1R)
复制标题
结合胰高血糖素样肽 1 受体 (GLP-1R) 七次跨膜结构域的结构决定因素
DOI：
10.1074/jbc.m116.721977
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发表时间：
2016-06-17
影响因子：
4.8
通讯作者：
Wang, Ming-Wei
中科院分区：
文献类型：
--
作者：
Yang, Dehua;de Graaf, Chris;Wang, Ming-Wei
胰升糖素样肽-1受体(GLP-1R)属于G蛋白偶联受体中的分泌素样受体(B类)家族。B类家族的成员以其大的胞外结构域而异，该结构域与典型的七跨膜(7TM)螺旋结构域协同工作，以响应各种肽激素的结合。我们将基于结构的定点突变研究与GLP-1R与多个多肽配体变体结合的全长模型的分子动力学模拟相结合。尽管GLP-1R与其最接近的结构同源物--胰高血糖素受体(GCGR)有很高的序列相似性，但在62个稳定表达的突变体中，近一半以不同于GCGR的相应突变体的方式影响GLP-1R。对野生型和突变型GLP-1R中心点配体复合体的分子动力学模拟提供了GLP-1R通过7TM口袋中的残基识别GLP-1R N末端的分子机制，并解释了模拟GLP-1突变体如何恢复(模拟GCGR)GLP-1R突变体的结合亲和力。模拟的结构分析表明，7TM结合口袋中的多肽配体结合模式的变化是由于细胞外结构域相对于7TM束的移动而起作用的。这些结合模式的差异可能解释了GLP-1多肽变体之间的药理差异。
The glucagon-like peptide-1 receptor (GLP-1R) belongs to the secretin-like (class B) family of G protein-coupled receptors. Members of the class B family are distinguished by their large extracellular domain, which works cooperatively with the canonical seven-transmembrane (7TM) helical domain to signal in response to binding of various peptide hormones. We have combined structure-based site-specific mutational studies with molecular dynamics simulations of a full-length model of GLP-1R bound to multiple peptide ligand variants. Despite the high sequence similarity between GLP-1R and its closest structural homologue, the glucagon receptor (GCGR), nearly half of the 62 stably expressed mutants affected GLP-1R in a different manner than the corresponding mutants in GCGR. The molecular dynamics simulations of wild-type and mutant GLP-1R center dot ligand complexes provided molecular insights into GLP-1R-specific recognition mechanisms for the N terminus of GLP-1 by residues in the 7TM pocket and explained how glucagon-mimicking GLP-1 mutants restored binding affinity for (GCGR-mimicking) GLP-1R mutants. Structural analysis of the simulations suggested that peptide ligand binding mode variations in the 7TM binding pocket are facilitated by movement of the extracellular domain relative to the 7TM bundle. These differences in binding modes may account for the pharmacological differences between GLP-1 peptide variants.