Structural basis of μ-opioid receptor targeting by a nanobody antagonist

Jun Yu, Amit Kumar, Xuefeng Zhang, Charlotte Martin, Kevin Van holsbeeck, Pierre Raia, Antoine Koehl, Toon Laeremans, Jan Steyaert, Aashish Manglik, Steven Ballet, Andreas Boland () and Miriam Stoeber ()
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Jun Yu: University of Geneva
Amit Kumar: University of Geneva
Xuefeng Zhang: University of Geneva
Charlotte Martin: Vrije Universiteit Brussel
Kevin Van holsbeeck: Vrije Universiteit Brussel
Pierre Raia: University of Geneva
Antoine Koehl: University of California
Toon Laeremans: Confo Therapeutics N.V.
Jan Steyaert: Vrije Universiteit Brussel
Aashish Manglik: University of California
Steven Ballet: Vrije Universiteit Brussel
Andreas Boland: University of Geneva
Miriam Stoeber: University of Geneva

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract The μ-opioid receptor (μOR), a prototypical G protein-coupled receptor (GPCR), is the target of opioid analgesics such as morphine and fentanyl. Due to the severe side effects of current opioid drugs, there is considerable interest in developing novel modulators of μOR function. Most GPCR ligands today are small molecules, however biologics, including antibodies and nanobodies, represent alternative therapeutics with clear advantages such as affinity and target selectivity. Here, we describe the nanobody NbE, which selectively binds to the μOR and acts as an antagonist. We functionally characterize NbE as an extracellular and genetically encoded μOR ligand and uncover the molecular basis for μOR antagonism by determining the cryo-EM structure of the NbE-μOR complex. NbE displays a unique ligand binding mode and achieves μOR selectivity by interactions with the orthosteric pocket and extracellular receptor loops. Based on a β-hairpin loop formed by NbE that deeply protrudes into the μOR, we design linear and cyclic peptide analogs that recapitulate NbE’s antagonism. The work illustrates the potential of nanobodies to uniquely engage with GPCRs and describes lower molecular weight μOR ligands that can serve as a basis for therapeutic developments.

Date: 2024
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DOI: 10.1038/s41467-024-52947-6

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