Ding Yu, Zhang Huibing, Liao Yu-Ying, Chen Li-Nan, Ji Su-Yu, Qin Jiao, Mao Chunyou, Shen Dan-Dan, Lin Lin, Wang Hao, Zhang Yan, Li Xiao-Ming
Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Center of Brain Science and Brain-machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Cell Discov. 2022 Jun 7;8(1):55. doi: 10.1038/s41421-022-00420-3.
The intestinal hormone and neuromodulator cholecystokinin (CCK) receptors CCK1R and CCK2R act as a signaling hub in brain-gut axis, mediating digestion, emotion, and memory regulation. CCK receptors exhibit distinct preferences for ligands in different posttranslational modification (PTM) states. CCK1R couples to G and G, whereas CCK2R primarily couples to G. Here we report the cryo-electron microscopy (cryo-EM) structures of CCK1R-G signaling complexes liganded either by sulfated cholecystokinin octapeptide (CCK-8) or a CCK1R-selective small-molecule SR146131, and CCK2R-G complexes stabilized by either sulfated CCK-8 or a CCK2R-selective ligand gastrin-17. Our structures reveal a location-conserved yet charge-distinct pocket discriminating the effects of ligand PTM states on receptor subtype preference, the unique pocket topology underlying selectivity of SR146131 and gastrin-17, the conformational changes in receptor activation, and key residues contributing to G protein subtype specificity, providing multiple structural templates for drug design targeting the brain-gut axis.
肠道激素和神经调节剂胆囊收缩素（CCK）的受体CCK1R和CCK2R在脑-肠轴中作为信号枢纽，介导消化、情绪和记忆调节。CCK受体对处于不同翻译后修饰（PTM）状态的配体表现出不同的偏好。CCK1R与G和G偶联，而CCK2R主要与G偶联。在此，我们报告了由硫酸化胆囊收缩素八肽（CCK-8）或CCK1R选择性小分子SR146131配体的CCK1R-G信号复合物以及由硫酸化CCK-8或CCK2R选择性配体胃泌素-17稳定的CCK2R-G复合物的冷冻电子显微镜（cryo-EM）结构。我们的结构揭示了一个位置保守但电荷不同的口袋，该口袋区分配体PTM状态对受体亚型偏好的影响、SR146131和胃泌素-17选择性的独特口袋拓扑结构、受体激活中的构象变化以及对G蛋白亚型特异性有贡献的关键残基，为靶向脑-肠轴的药物设计提供了多个结构模板。
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