The human calcium-sensing receptor (CaSR) detects fluctuations in the extracellular Ca²⁺ concentration and maintains Ca²⁺ homeostasis^1,2. It also mediates diverse cellular processes not associated with Ca²⁺ balance^3,4,5. The functional pleiotropy of CaSR arises in part from its ability to signal through several G-protein subtypes⁶. We determined structures of CaSR in complex with G proteins from three different subfamilies: G_q, G_i and G_s. We found that the homodimeric CaSR of each complex couples to a single G protein through a common mode. This involves the C-terminal helix of each Gα subunit binding to a shallow pocket that is formed in one CaSR subunit by all three intracellular loops (ICL1–ICL3), an extended transmembrane helix 3 and an ordered C-terminal region. G-protein binding expands the transmembrane dimer interface, which is further stabilized by phospholipid. The restraint imposed by the receptor dimer, in combination with ICL2, enables G-protein activation by facilitating conformational transition of Gα. We identified a single Gα residue that determines G_q and G_s versus G_i selectivity. The length and flexibility of ICL2 allows CaSR to bind all three Gα subtypes, thereby conferring capacity for promiscuous G-protein coupling.

人钙敏感受体 (CaSR) 检测细胞外 Ca ²⁺浓度的波动并维持 Ca ²⁺稳态^1,2。它还介导与 Ca ²⁺平衡无关的多种细胞过程^3,4,5。 CaSR 的功能多效性部分源于其通过几种 G 蛋白亚型发出信号的能力⁶。我们确定了 CaSR 与来自三个不同亚家族的 G 蛋白复合物的结构：G _q、G _i和 G _s。我们发现每个复合物的同源二聚体 CaSR 通过共同模式与单个 G 蛋白偶联。这涉及每个 Gα 亚基的 C 端螺旋与浅袋结合，该浅袋由所有三个细胞内环 (ICL1–ICL3)、延伸的跨膜螺旋 3 和有序的 C 端区域在一个 CaSR 亚基中形成。 G 蛋白结合扩大了跨膜二聚体界面，磷脂进一步稳定了该界面。受体二聚体施加的限制与 ICL2 结合，通过促进 Gα 的构象转变来激活 G 蛋白。我们确定了一个 Gα 残基，它决定了 G _q和 G _s与 G _{i 的}选择性。 ICL2 的长度和灵活性允许 CaSR 结合所有三种 Gα 亚型，从而赋予混杂 G 蛋白偶联的能力。