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Publication Abstract from PubMed

Morphine and fentanyl are among the most used opioid drugs that confer analgesia and unwanted side effects through both G protein and arrestin signaling pathways of mu-opioid receptor (muOR). Here, we report structures of the human muOR-G protein complexes bound to morphine and fentanyl, which uncover key differences in how they bind the receptor. We also report structures of muOR 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 muOR promoted by morphine and fentanyl. Ligands designed to reduce TM6/7 interactions display preferential G protein signaling. Our results provide crucial insights into fentanyl recognition and signaling of muOR, which may facilitate rational design of next-generation analgesics.

Molecular recognition of morphine and fentanyl by the human mu-opioid receptor.,Zhuang Y, Wang Y, He B, He X, Zhou XE, Guo S, Rao Q, Yang J, Liu J, Zhou Q, Wang X, Liu M, Liu W, Jiang X, Yang D, Jiang H, Shen J, Melcher K, Chen H, Jiang Y, Cheng X, Wang MW, Xie X, Xu HE Cell. 2022 Nov 10;185(23):4361-4375.e19. doi: 10.1016/j.cell.2022.09.041. PMID:36368306^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.