Two-thirds of human hormones and one-third of clinical drugs activate ~350 G-protein-coupled receptors (GPCR) belonging to four classes: A, B1, C and F. Whereas a model of activation has been described for class A, very little is known about the activation of the other classes, which differ by being activated by endogenous ligands bound mainly or entirely extracellularly. Here we show that, although they use the same structural scaffold and share several ‘helix macroswitches’, the GPCR classes differ in their ‘residue microswitch’ positions and contacts. We present molecular mechanistic maps of activation for each GPCR class and methods for contact analysis applicable for any functional determinants. This provides a superfamily residue-level rationale for conformational selection and allosteric communication by ligands and G proteins, laying the foundation for receptor-function studies and drugs with the desired modality.

三分之二的人类激素和三分之一的临床药物可激活约 350 个 G 蛋白偶联受体 (GPCR)，分为四类：A、B1、C 和 F。虽然已经描述了 A 类的激活模型，对于其他类别的激活知之甚少，其不同之处在于主要或完全在细胞外结合的内源配体被激活。在这里，我们表明，尽管它们使用相同的结构支架并共享多个“螺旋宏开关”，但 GPCR 类别的“残留微开关”位置和接触有所不同。我们提出了每个 GPCR 类别的激活分子机制图以及适用于任何功能决定因素的接触分析方法。这为配体和 G 蛋白的构象选择和变构通讯提供了超家族残基水平的基本原理，为受体功能研究和具有所需模式的药物奠定了基础。