Cryo-EM structure of small-molecule agonist bound delta opioid receptor-Gi complex enables discovery of biased compound
Lin Cheng, Zhuang Miao, Sicen Liu, Zhe Li, Hong Fu, Chanjuan Xu, Shilong Hu, Chang Zhao, Yuxuan Liu, Tiantian Zhao, Wen‐Cheng Liu, Heli Wang, Runduo Liu, Wei Yan, Xiangdong Tang, Jianfeng Liu, Zhenhua Shao, Bowen Ke
Abstract
Delta opioid receptor (δOR) plays a pivotal role in modulating human sensation and emotion. It is an attractive target for drug discovery since, unlike Mu opioid receptor, it is associated with low risk of drug dependence. Despite its potential applications, the pharmacological properties of δOR, including the mechanisms of activation by small-molecule agonists and the complex signaling pathways it engages, as well as their relation to the potential side effects, remain poorly understood. In this study, we use cryo-electron microscopy (cryo-EM) to determine the structure of the δOR-Gi complex when bound to a small-molecule agonist (ADL5859). Moreover, we design a series of probes to examine the key receptor-ligand interaction site and identify a region involved in signaling bias. Using ADL06 as a chemical tool, we elucidate the relationship between the β-arrestin pathway of the δOR and its biological functions, such as analgesic tolerance and convulsion activities. Notably, we discover that the β-arrestin recruitment of δOR might be linked to reduced gastrointestinal motility. These insights enhance our understanding of δOR’s structure, signaling pathways, and biological functions, paving the way for the structure-based drug discovery. The delta opioid receptor (δOR) is key in modulating sensation and emotion with a lower risk of drug dependence. Here, authors report cryo-EM structure of δOR and design probes to explore its signaling bias, with insights for drug discovery.