Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors

@article{Yin2016StructureAL,
  title={Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors},
  author={Jie Yin and Kerim Babaoglu and Chad A. Brautigam and Lindsay D Clark and Zhenhua Shao and Thomas H. Scheuermann and Charles M. Harrell and Anthony L Gotter and Anthony J. Roecker and Christopher J Winrow and John J. Renger and Paul J. Coleman and Daniel M. Rosenbaum},
  journal={Nature Structural \&Molecular Biology},
  year={2016},
  volume={23},
  pages={293-299}
}
The orexin (also known as hypocretin) G protein–coupled receptors (GPCRs) regulate sleep and other behavioral functions in mammals, and are therapeutic targets for sleep and wake disorders. The human receptors hOX1R and hOX2R, which are 64% identical in sequence, have overlapping but distinct physiological functions and potential therapeutic profiles. We determined structures of hOX1R bound to the OX1R-selective antagonist SB-674042 and the dual antagonist suvorexant at 2.8-Å and 2.75… 
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Crystal Structures of Human Orexin 2 Receptor Bound to the Subtype-Selective Antagonist EMPA.

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The potential of structure-based drug design to develop more subtype-selective GPCR ligands with potentially reduced side effects and provides an attractive probe molecule and lead compound is demonstrated.

The Human Orexin/Hypocretin Receptor Crystal Structures.

The orexin/hypocretin receptor coordinates are made available, now available to the broader academic and drug discovery community, to facilitate rational design of new therapeutics that modulate orex in/hyporetin signaling in humans.

Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation

Cryo-electron microscopy structures of active-state OX2R bound to an endogenous peptide agonist and a small-molecule agonist enable structure-based discovery of therapeutic orexin agonists for the treatment of NT1 and other hypersomnia disorders.

Molecular basis for anti-insomnia drug design from structure of lemborexant-bound orexin 2 receptor.

Structural basis for ligand recognition of the neuropeptide Y Y2 receptor.

The crystal structure of Y2R bound to a selective antagonist JNJ-31020028 is reported at 2.8 Å resolution and reveals molecular details of the ligand-binding mode of Y1R, deepening understanding about molecular mechanisms of ligand recognition and subtype specificity of NPY receptors and enabling structure-based drug design.

Pharmacophore Model To Discover OX1 and OX2 Orexin Receptor Ligands.

A pharmacophore model trained on ∼200 antagonists and prospectively validated by screening a collection of ∼137,000 compounds is reported, finding two subpockets are important for activation in the OX1 and OX2 receptor system.

Structure-Based Discovery of Novel Ligands for the Orexin 2 Receptor.

The orexin receptors are peptide-sensing G protein-coupled receptors that are intimately linked with regulation of the sleep/wake cycle. We used a recently solved X-ray structure of the orexin…

Therapeutics development for addiction: Orexin-1 receptor antagonists

Orexin Receptor Multimerization versus Functional Interactions: Neuropharmacological Implications for Opioid and Cannabinoid Signalling and Pharmacogenetics

Evidence for functional interactions and/or heterodimerization between wild-type and variant orexin receptors and opioid and cannabinoid receptors is discussed in the context of its relevance to depression and epilepsy.
...

References

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