Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China.
Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China.
Cell Chem Biol. 2023 Nov 16;30(11):1343-1353.e5. doi: 10.1016/j.chembiol.2023.08.003. Epub 2023 Sep 5.
CD97 (ADGRE5) is an adhesion G protein-coupled receptor (aGPCR) which plays crucial roles in immune system and cancer. However, the mechanism of CD97 activation and the determinant of G coupling selectivity remain unknown. Here, we present the cryo-electron microscopy structures of human CD97 in complex with G, G, and G. Our structures reveal the stalk peptide recognition mode of CD97, adding missing information of the current tethered-peptide activation model of aGPCRs. For instance, a revised "FXφφφ" motif and a framework of conserved aromatic residues in the ligand-binding pocket. Importantly, structural comparisons of G, G, and G engagements of CD97 reveal key determinants of G coupling selectivity, where a deep insertion of the α helix 5 and a closer contact with the transmembrane helix 6, 5, and 3 dictate coupling preferences. Taken together, our structural study of CD97 provides a framework for understanding CD97 signaling and the G coupling selectivity.
CD97（ADGRE5）是一种粘附 G 蛋白偶联受体（aGPCR），在免疫系统和癌症中发挥着关键作用。然而，CD97 的激活机制和 G 偶联选择性的决定因素仍不清楚。在这里，我们展示了与人 CD97 复合物的冷冻电镜结构，包括 G、G 和 G。我们的结构揭示了 CD97 识别柄肽的模式，补充了当前 aGPCR tethered-peptide 激活模型中缺失的信息。例如，一个修正的“FXφφφ”基序和配体结合口袋中保守芳香残基的框架。重要的是，对 CD97 与 G、G 和 G 的结构比较揭示了 G 偶联选择性的关键决定因素，其中α螺旋 5 的深插入和与跨膜螺旋 6、5 和 3 的更紧密接触决定了偶联偏好。总之，我们对 CD97 的结构研究为理解 CD97 信号转导和 G 偶联选择性提供了一个框架。
