Conformational transitions and activation of the adhesion receptor CD97

Adhesion G protein-coupled receptors (aGPCRs) are evolutionarily ancient receptors involved in a variety of physiological and pathophysiological processes. Modulators of aGPCR, particularly antagonists, hold therapeutic promise for diseases like cancer and immune and neurological disorders. Hindered by the inactive state structural information, our understanding of antagonist development and aGPCR activation faces challenges. Here, we report the cryo-electron microscopy structures of human CD97, a prototypical aGPCR that plays crucial roles in immune system, in its inactive apo and G13-bound fully active states. Compared with other family GPCRs, CD97 adopts a compact inactive conformation with a constrained ligand pocket. Activation induces significant conformational changes for both extracellular and intracellular sides, creating larger cavities for Stachel sequence binding and G13 engagement. Integrated with functional and metadynamics analyses, our study provides significant mechanistic insights into the activation and signaling of aGPCRs, paving the way for future drug discovery efforts. [Display omitted] •Cryo-EM structures of human CD97 in both inactive and active states are studied•We elucidate the binding modes of the Stachel sequence of aGPCR in both states•We uncover the conformational transitions involved in aGPCR activation•We decode the conserved activation-related motifs of aGPCRs Mao et al. use cryo-EM to uncover adhesion G protein-coupled receptor (aGPCR) intricacies. These ancient receptors, crucial in physiology, offer therapeutic potential for diseases like cancer. Hindered by the knowledge gap in structural information, we face challenges in understanding antagonist development and aGPCR activation The research unveils cryo-EM structures of CD97 in both inactive and fully active states. CD97, unlike other GPCRs, has a compact inactive form. Activation induces changes, creating cavities for binding and engagement. Integrated analyses provide insights, paving the way for aGPCR modulation in drug discovery. Cryo-EM structures of human CD97 in its inactive apo and G13-bound fully active states provide mechanistic insights into the activation and drug development of aGPCRs.