Cholecystokinin receptors, CCK_AR and CCK_BR, are important neurointestinal peptide hormone receptors and play a vital role in food intake and appetite regulation. Here, we report three crystal structures of the human CCK_AR in complex with different ligands, including one peptide agonist and two small-molecule antagonists, as well as two cryo-electron microscopy structures of CCK_BR–gastrin in complex with G_i2 and G_q, respectively. These structures reveal the recognition pattern of different ligand types and the molecular basis of peptide selectivity in the cholecystokinin receptor family. By comparing receptor structures in different conformational states, a stepwise activation process of cholecystokinin receptors is proposed. Combined with pharmacological data, our results provide atomic details for differential ligand recognition and receptor activation mechanisms. These insights will facilitate the discovery of potential therapeutics targeting cholecystokinin receptors.

胆囊收缩素受体 CCK _A R 和 CCK _B R 是重要的神经肠肽激素受体，在食物摄入和食欲调节中起着至关重要的作用。_{在这里，我们报告了与不同配体复合的人 CCK A} R的三种晶体结构，包括一种肽激动剂和两种小分子拮抗剂，以及与 G _{i2复合的 CCK B} R-胃泌素的两种低温电子显微镜结构和_Gq， 分别。这些结构揭示了不同配体类型的识别模式和缩胆囊素受体家族中肽选择性的分子基础。通过比较不同构象状态下的受体结构，提出了胆囊收缩素受体的逐步激活过程。结合药理学数据，我们的结果为差异配体识别和受体激活机制提供了原子细节。这些见解将有助于发现针对胆囊收缩素受体的潜在疗法。