Orexin and Orexin receptor

spinqualitylabelsall models Human orexin receptor complex with insomnia medication belsomra and oleic acid (PDB code 4s0v) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Function The orexin neuropeptides, Orexin-A and Orexin-B, can excite neurons in the brain and affect multiple systems, including the acetylcholine, dopamine, histamine, and norepinephrine systems . These orexin neuropeptides bind to two subtypes of orexin receptors, Orexin receptor 1 and Orexin receptor 2, both of which are G protein-coupled receptors (GPCRs) . The GPCRs can sense a molecule outside the cell and send a signal through transduction in order to cause the cells to respond . Thus, binding of the two can control wakefulness in humans. In studies, Orexin-B has shown to be more selective in binding, choosing to bind to Orexin receptor type 2 a majority of the time. Orexin-A has shown an equal selectivity at both types of receptors . See also Hypocretin and receptors Transmembrane (cell surface) receptors Disease Defects in orexin signaling are responsible for the human diseases of narcolepsy and insomnia. Relevance Belsomra or Suvorexant is a dual orexin receptor antagonist, and has the ability to block both Orexin receptors 1 and 2, thus inhibiting the neuropeptides from binding. By blocking this interaction, sleep can occur . Structural highlights The suvorexant-binding pocket is open to the extracellular space through a constricted solvent-accessible channel. A complex network of electrostatic interactions includes salt bridges between the protein and the drug, on both sides of the entry channel. See also: Receptor Transmembrane (cell surface) receptors G protein-coupled receptors

3D Structures of orexin and orexin receptor

Updated on 20-August-2023

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• Orexin
  • G protein-coupled receptors, Hypocretin and receptors – hOrx-A – human - NMR
    
  • Transmembrane (cell surface) receptors – hOrx-B - NMR
    
  • Belsomra – hOrx-B + antibody
    
• Orexin receptor
  • Receptor – hOrxR-1 (mutant) + EMPA
    
  • Transmembrane (cell surface) receptors, G protein-coupled receptors, 6tq7 – hOrxR-1 (mutant) + pyridine derivative
    
  • 6tp4 – hOrxR-1 (mutant) + pyrrolydine derivative
    
  • 6tq4 – hOrxR-1 (mutant) + benzoxazole derivative
    
  • 6tq9 – hOrxR-1 (mutant) + quinoline derivative
    
  • 6tot, 6to7, 6tp3, 6tp6 – hOrxR-1 (mutant) + insomnia drug
    
  • 4s0v – hOrxR-1/glycogen synthase + insomnia drug
    
  • 4zj8, 4zjc, 5wqc, 5ws3, 6tpg, 6v9s – hOrxR-1/glycogen synthase + antagonist
    
  • 7xrr – hOrxR-2 + insomnia drug
    
  • 7sqoj, 7sr8 – hOrxR-2 + Gi + nanobody + wake-promoting drug – Cryo EM
    
  • 6tpj – hOrxR-2/glycogen synthase (mutant) + insomnia drug
    
  • 6tpn – hOrxR-2/glycogen synthase + antagonist
    
  • 7l1u, 7l1v – mOrxR-2 + G protein + nanobody + agonist – Cryo EM
    

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Michal Harel, Alexander Berchansky