Crystal structure of the GLP-1 receptor bound to a peptide agonist
Crystal structure of the GLP-1 receptor bound to a peptide agonist
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DOI：
10.1038/nature22800
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发表时间：
2017-06-08
期刊：
影响因子：
64.8
通讯作者：
Marshall, Fiona H.
中科院分区：
文献类型：
--
作者：
Jazayeri, Ali;Rappas, Mathieu;Marshall, Fiona H.
胰高血糖素样肽1 （GLP-1）通过控制胰岛素从胰腺释放调节葡萄糖稳态。GLP-1肽激动剂是治疗糖尿病的有效药物。为了深入了解GLP-1肽的分子作用机制，我们报道了与截断肽激动剂结合的全长GLP-1受体的晶体结构。肽激动剂保持a-螺旋构象，因为它位于受体结合袋的深处。跨膜螺旋的排列揭示了类似于在A类受体中观察到的活性构象的特征。在这种结构信息的指导下，我们设计了在糖尿病小鼠模型中具有有效体内活性的肽激动剂。
Glucagon-like peptide 1 (GLP-1) regulates glucose homeostasis through the control of insulin release from the pancreas. GLP-1 peptide agonists are efficacious drugs for the treatment of diabetes. To gain insight into the molecular mechanism of action of GLP-1 peptides, here we report the crystal structure of the full-length GLP-1 receptor bound to a truncated peptide agonist. The peptide agonist retains an a-helical conformation as it sits deep within the receptor-binding pocket. The arrangement of the transmembrane helices reveals hallmarks of an active conformation similar to that observed in class A receptors. Guided by this structural information, we design peptide agonists with potent in vivo activity in a mouse model of diabetes.