Structures of the entire human opioid receptor family

Highlights

• •Structures of the entire family of human opioid receptors with opioid peptides
• •The N-terminal “YGGF” message motif of opioid peptides drives receptor activation
• •The C-terminal sequence variations of opioid peptides address receptor selectivity
• •Extracellular loop 2 is key for opioid receptors to filter specific opioid peptides

Summary

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 biochemicaesign of safer opioid drugs for pain relief.