Molecular control of δ-opioid receptor signalling

摘要: Opioids represent widely prescribed and abused medications, although their signal transduction mechanisms are not well understood. Here we present the 1.8 A high-resolution crystal structure of human δ-opioid receptor (δ-OR), revealing presence fundamental role a sodium ion in mediating allosteric control functional selectivity constitutive activity. The distinctive δ-OR site architecture is centrally located polar interaction network seven-transmembrane bundle core, with stabilizing reduced agonist affinity state, thereby modulating transduction. Site-directed mutagenesis studies reveal that changing residue Asn 131 to an alanine or valine augments β-arrestin-mediated signalling. Asp95Ala, Asn310Ala Asn314Ala mutations transform classical antagonists such as naltrindole into potent β-arrestin-biased agonists. data establish molecular basis for opioid signalling, sodium-coordinating residues act ‘efficacy switches’ at prototypic G-protein-coupled receptor. 1.8 A X-ray presented, site-directed crucial this Opioid receptors mediate actions endogenous exogenous opioids many physiological processes, including analgesia, consciousness, motor mood. This paper reports resolution, seems show mutating key amino acids transforms antagonist agonist. Also apparent sodium-binding pocket could aid development subtype-selective agonists — extension orthosteric ligands generate 'bitopic' orthosteric/allosteric compounds more favourable pharmacological properties.