| Summary: | The μ opioid receptor plays a key role in mediating the physiological, pharmacological, and behavioral effects of endogenous opioids and of opiate drugs such as morphine and heroin. This study examines the structural features critical to the selective binding of μ ligands to the μ receptor as opposed to the other two highly homologous opioid receptors, δ and κ. We use a series of chimeric constructs between the μ and either the δ or the κ receptors to investigate the structural bases of binding selectivity of multiple classes of μ-selective ligands. Our results demonstrate that a region comprising the sixth transmembrane domain and the third extracellular loop is critical for the μ/κ discrimination by all μ-selective ligands. This region is also critical for μ/δ discrimination by the μ antagonists. However, μ agonists, particularly the peptides, exhibit more complex interactions, often relying on the N-terminal region surrounding the first extracellular loop for μ/δ discrimination. Thus, the same μ peptide ligand depends on different parts of the receptor to discriminate between μ and δ receptors on the one hand and μ and κ on the other. In general, antagonists show the most consistent discrimination mechanisms regardless of construct, whereas agonists, particularly peptides, achieve selectivity by interacting with numerous domains of the receptors.
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