Molecular recognition of morphine and fentanyl by the human μ-opioid receptor

Morphine and fentanyl are among the most used opioid drugs that confer analgesia and unwanted side ef-fects through both G protein and arrestin signaling pathways of mu-opioid receptor (mu OR). Here, we report structures of the human mu OR-G protein complexes bound to morphine and fentanyl, which uncover key dif-ferences in how they bind the receptor. We also report structures of mu OR bound to TRV130, PZM21, and SR17018, which reveal preferential interactions of these agonists with TM3 side of the ligand-binding pocket rather than TM6/7 side. In contrast, morphine and fentanyl form dual interactions with both TM3 and TM6/7 regions. Mutations at the TM6/7 interface abolish arrestin recruitment of mu OR promoted by morphine and fen-tanyl. Ligands designed to reduce TM6/7 interactions display preferential G protein signaling. Our results provide crucial insights into fentanyl recognition and signaling of mu OR, which may facilitate rational design of next-generation analgesics.

Automated summary

This study reports the structural differences in the binding of morphine and fentanyl to the human mu-opioid receptor (mu OR), as well as the preferential interactions of other agonists with specific regions of the receptor. Mutations at certain regions abolish the recruitment of arrestin by morphine and fentanyl. Ligands designed to reduce interactions with specific regions display preferential G protein signaling. These findings provide crucial insights into the recognition and signaling of fentanyl, which could aid in the rational design of next-generation analgesics.