CD97 (ADGRE5) 是一种粘附G蛋白偶联受体 (aGPCR)，在免疫系统和癌症中起着关键作用。然而，CD97的激活机制和G13偶联选择性的决定因素目前尚不清楚。在这里，我们提供了人类CD97与G13、Gq和Gs复合物的冷冻电子显微镜结构。我们的结构揭示了CD97的柄肽识别模式，补充了目前关于aGPCR的系缚肽激活模型的缺失信息。例如，修订的"FXφφφ"基序和配体结合口袋中保守芳香残基的框架。重要的是，CD97与G13、Gq和Gs的结构比较揭示了G13偶联选择性的关键因素，其中α螺旋5的深入插入和与跨膜螺旋6、5和3的更紧密接触决定了偶联偏好。综上所述，我们对CD97的结构研究为理解CD97信号传导和G13偶联选择性提供了一个框架。版权所有 © 2023 Elsevier Ltd. 保留所有权利。

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 G13 coupling selectivity remain unknown. Here, we present the cryo-electron microscopy structures of human CD97 in complex with G13, Gq, and Gs. 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 G13, Gq, and Gs engagements of CD97 reveal key determinants of G13 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 G13 coupling selectivity.Copyright © 2023 Elsevier Ltd. All rights reserved.