µ-Opiod Receptor
µ-Opiod Receptor
The μ-opioid receptor (μOR) is a G protein-coupled receptor (GPCR) that belongs to the opioid receptor (OR) family. ORs are involved in pain modulation and analgesia, with the μOR subtype being the primary therapeutic target for pain relief.
Opioid compounds like morphine and fentanyl are clinically used small molecule drugs for acute pain treatment that target the μOR receptor. However, these substances are highly addictive and cause severe side effects such as respiratory depression. Due to their over-prescription and illegal abuse, synthetic opioids are causing an alarming opioid overdose epidemic. As a result, there is an urgent need to develop novel and safer μOR .
While small-molecule ligands have dominated the landscape of μOR-targeting drugs, no biologics have been in-depth characterized to date for this target. Discovering innovative μOR modulators could offer distinct advantages and hold promise for innovative therapeutic strategies.
A recent study has functionally and structurally characterized a μOR-targeting nanobody (NbE) ligand that selectively binds the GPCR and acts as an antagonist, uncovering its unique molecular mechanism. The structural analysis led to the development of peptide analogs derived from NbE, that could pave the way for innovative therapies.
Structural basis for μOR antagonism: Key Insights
Discover and easily visualize new Cryo-EM structural insights of μOR in complex with nanobody (Nbe) in this video. Video created with the 3decision software.
Based on the study from Yu et al., the Cryo-EM structure (3.1 Å) of the NbE-μOR complex revealed an extended and unique interaction network: NbE inserts deeply into the orthosteric pocket and additionally engages with extracellular loops (ECLs) of μOR, stabilizing the receptor in an inactive conformation (see video above).
The structural study elucidated notable insights:
NbE engages the μOR orthosteric binding pocket in an unprecedented binding mode, offering new possibilities for structure-guided drug design. The μOR residues crucial for the observed high affinity are D147, L219, and W318.
The engagement of NbE with the μOR extracellular loops explains the OR subtype selectivity, as ECLs are highly variable regions within the OR family. In particular, ECL2 and ECL3 critically contribute to the high-affinity binding.
Based on the structural information obtained, the researchers developed several peptide analogs, derived from the nanobody. Among these, some cyclic, constrained peptides retained μOR-selective antagonism with an affinity comparable to that of NbE.
These insights provide novel opportunities for structure-based design of new and improved μOR ligands.
Nanobodies (Nbs)
Nanobodies (Nbs) are a single-domain antibody fragments derived from heavy chain-only antibodies, naturally occurring in some animal classes such as camelids. They are characterized by small size, high antigen binding affinity and selectivity.
Reference
Yu, J., Kumar, A., Zhang, X. et al. Structural basis of μ-opioid receptor targeting by a nanobody antagonist. Nat Commun 15, 8687 (2024). https://doi.org/10.1038/s41467-024-52947-6