Opioids are effective analgesics, but their use is beset by serious side effects, including addiction and respiratory depression, which contribute to the ongoing opioid crisis. The human opioid system contains four opioid receptors (μOR, δOR, κOR, and NOPR) and a set of related endogenous opioid peptides (EOPs), which show distinct selectivity toward their respective opioid receptors (ORs). Despite being key to the development of safer analgesics, the mechanisms of molecular recognition and selectivity of EOPs to ORs remain unclear. Here, we systematically characterize the binding of EOPs to ORs and present five structures of EOP-OR-G_i complexes, including β-endorphin- and endomorphin-bound μOR, deltorphin-bound δOR, dynorphin-bound κOR, and nociceptin-bound NOPR. These structures, supported by biochemical results, uncover the specific recognition and selectivity of opioid peptides and the conserved mechanism of opioid receptor activation. These results provide a structural framework to facilitate rational design of safer opioid drugs for pain relief.

阿片类药物是有效的镇痛药，但其使用受到严重副作用的困扰，包括成瘾和呼吸抑制，这导致了持续的阿片类药物危机。人类阿片系统包含四种阿片受体（μOR、δOR、κOR 和 NOPR）和一组相关的内源性阿片肽（EOP），它们对各自的阿片受体（OR）表现出不同的选择性。尽管 EOP 是开发更安全镇痛药的关键，但 EOP 对 OR 的分子识别和选择性机制仍不清楚。在这里，我们系统地表征了 EOP 与 OR 的结合，并提出了 EOP-OR-G _i复合物的五种结构，包括 β-内啡肽和内吗啡结合的 μOR、deltorphin 结合的 δOR、强啡肽结合的 κOR 和伤害感受素结合的 NOPR 。这些结构在生化结果的支持下，揭示了阿片肽的特异性识别和选择性以及阿片受体激活的保守机制。这些结果提供了一个结构框架，以促进合理设计更安全的阿片类药物来缓解疼痛。