Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Department of Otolaryngology Head and Neck Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
Nat Commun. 2024 Sep 27;15(1):8284. doi: 10.1038/s41467-024-52601-1.
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-G 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.
德尔塔阿片受体（δOR）在调节人类感觉和情绪方面起着关键作用。它是药物发现的一个有吸引力的靶点，因为与μ阿片受体不同，它与药物依赖的低风险相关。尽管具有潜在的应用前景，但 δOR 的药理学特性，包括小分子激动剂激活的机制和它所涉及的复杂信号通路，以及它们与潜在副作用的关系，仍然知之甚少。在这项研究中，我们使用冷冻电子显微镜（cryo-EM）来确定 δOR-G 复合物与小分子激动剂（ADL5859）结合时的结构。此外，我们设计了一系列探针来检查关键的受体-配体相互作用位点，并确定一个参与信号偏向的区域。使用 ADL06 作为化学工具，我们阐明了 δOR 的β-arrestin 途径与其生物学功能（如镇痛耐受和惊厥活性）之间的关系。值得注意的是，我们发现 δOR 的β-arrestin 募集可能与胃肠道蠕动减少有关。这些见解增强了我们对 δOR 结构、信号通路和生物学功能的理解，为基于结构的药物发现铺平了道路。
