Choosing a partner that fits G protein–coupled receptors (GPCRs) are responsible for transducing diverse signals from outside to inside cells. This process requires specificity both in ligand binding to GPCRs and in coupling between GPCRs and their intracellular partners, G proteins. Qiao et al. determined the structure of the human glucagon receptor (GCGR), a type B GPCR, bound to glucagon and one of two heterotrimeric G proteins, Gs or Gi1. GCGR signals mainly through Gs, and the structures provide a basis for this specificity. Conformational changes in GCGR, relative to the inactive state, create a binding cavity for the G proteins. The pocket is opened sufficiently to accommodate a bulky binding motif in Gs. Gi1 can still bind but the pocket does not close around it, so there is a smaller interaction interface. Science, this issue p. 1346 Structures of a G protein–coupled receptor bound to two different G proteins reveal molecular details that govern G protein selectivity. Class B G protein–coupled receptors, an important class of therapeutic targets, signal mainly through the Gs class of heterotrimeric G proteins, although they do display some promiscuity in G protein binding. Using cryo–electron microscopy, we determined the structures of the human glucagon receptor (GCGR) bound to glucagon and distinct classes of heterotrimeric G proteins, Gs or Gi1. These two structures adopt a similar open binding cavity to accommodate Gs and Gi1. The Gs binding selectivity of GCGR is explained by a larger interaction interface, but there are specific interactions that affect Gi more than Gs binding. Conformational differences in the receptor intracellular loops were found to be key selectivity determinants. These distinctions in transducer engagement were supported by mutagenesis and functional studies.

中文翻译：

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人胰高血糖素受体识别 Gs 和 Gi 的结构基础

选择适合 G 蛋白偶联受体 (GPCR) 的伙伴负责将不同的信号从细胞外转入细胞内。该过程需要在配体与 GPCR 的结合以及 GPCR 与其细胞内伙伴 G 蛋白之间的耦合方面具有特异性。乔等人。确定了人类胰高血糖素受体 (GCGR) 的结构，这是一种 B 型 GPCR，与胰高血糖素和两种异源三聚体 G 蛋白 Gs 或 Gi1 中的一种结合。GCGR 主要通过 Gs 发出信号，结构为这种特异性提供了基础。GCGR 中的构象变化，相对于非活动状态，为 G 蛋白创造了一个结合腔。口袋被充分打开以容纳 Gs 中庞大的结合基序。Gi1仍然可以绑定，但口袋没有关闭，所以交互界面更小。科学，这个问题 p。1346 与两种不同 G 蛋白结合的 G 蛋白偶联受体的结构揭示了控制 G 蛋白选择性的分子细节。BG 类蛋白偶联受体是一类重要的治疗靶点，主要通过异源三聚体 G 蛋白的 Gs 类发出信号，尽管它们在 G 蛋白结合方面确实表现出一些混杂性。使用冷冻电子显微镜，我们确定了与胰高血糖素结合的人胰高血糖素受体 (GCGR) 和不同类别的异源三聚体 G 蛋白 Gs 或 Gi1 的结构。这两种结构采用类似的开放式结合腔来容纳 Gs 和 Gi1。GCGR 的 Gs 结合选择性可以通过更大的相互作用界面来解释，但有一些特定的相互作用比 Gs 结合更能影响 Gi。发现受体细胞内环的构象差异是关键的选择性决定因素。诱变和功能研究支持了换能器参与的这些区别。