8EF5

Fentanyl-bound mu-opioid receptor-Gi complex

Summary for 8EF5

• Entry DOI: 10.2210/pdb8ef5/pdb
• EMDB information: 28066 28069 28077 28085 28086 28088
• Descriptor: Mu-type opioid receptor, Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (7 entities in total)
• Functional Keywords: mu-opioid receptor, g protein, fentanyl, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 7
• Total formula weight: 240566.89

Authors

Zhuang, Y.,Wang, Y.,Guo, S.,Zhou, X.E.,Rao, Q.,He, X.,He, B.,Liu, J.,Zhou, Q.,Wang, X.,Liu, W.,Jiang, X.,Yang, D.,Chen, X.,Jiang, Y.,Jiang, H.,Shen, J.,Melcher, K.,Wang, M.,Xie, X.,Xu, H.E. (deposition date: 2022-09-08, release date: 2022-11-09, Last modification date: 2025-05-14)

Primary citation

Zhuang, Y.,Wang, Y.,He, B.,He, X.,Zhou, X.E.,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, M.W.,Xie, X.,Xu, H.E.
Molecular recognition of morphine and fentanyl by the human mu-opioid receptor.
Cell, 185:4361-4375.e19, 2022

PubMed Abstract: 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 μ-opioid receptor (μOR). Here, we report structures of the human μOR-G protein complexes bound to morphine and fentanyl, which uncover key differences in how they bind the receptor. We also report structures of μOR 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 μOR 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 μOR, which may facilitate rational design of next-generation analgesics.

PubMed: 36368306
DOI: 10.1016/j.cell.2022.09.041

Experimental method

ELECTRON MICROSCOPY (3.3 Å)