G protein–coupled receptors (GPCRs) are key regulators of information transmission between cells and organs. Despite this, we have only a limited understanding of the behavior of GPCRs in the apo state and the conformational changes upon agonist binding that lead to G protein recruitment and activation. We expressed and purified unmodified apo and peptide-bound calcitonin gene–related peptide (CGRP) receptors from insect cells to determine their cryo–electron microscopy (cryo-EM) structures, and we complemented these with analysis of protein conformational dynamics using hydrogen-deuterium exchange mass spectrometry and three-dimensional variance analysis of the cryo-EM data. Together with our previously published structure of the active, Gs-bound CGRP receptor complex, our work provides insight into the mechanisms of class B1 GPCR activation.

G蛋白偶联受体（GPCR）是细胞和器官之间信息传递的关键调节器。尽管如此，我们对载脂蛋白状态下GPCR的行为以及激动剂结合后导致G蛋白募集和激活的构象变化的认识仍然有限。我们从昆虫细胞中表达和纯化了未修饰的载脂蛋白和与肽结合的降钙素基因相关肽（CGRP）受体，以确定它们的冷冻电子显微镜（cryo-EM）结构，并通过使用氢-氘进行蛋白质构象动力学分析来补充这些结构交换质谱法和低温电磁数据的三维方差分析。连同我们先前发布的，与Gs结合的活性CGRP活性复合物的结构一起，我们的工作提供了对B1类GPCR激活机制的洞察力。