4S0V: Crystal Structure Of The Human Ox2 Orexin Receptor Bound To The Insomnia Drug Suvorexant

Citation:
Abstract
The orexin (also known as hypocretin) G protein-coupled receptors (GPCRs) respond to orexin neuropeptides in the central nervous system to regulate sleep and other behavioural functions in humans. Defects in orexin signalling are responsible for the human diseases of narcolepsy and cataplexy; inhibition of orexin receptors is an effective therapy for insomnia. The human OX2 receptor (OX2R) belongs to the beta branch of the rhodopsin family of GPCRs, and can bind to diverse compounds including the native agonist peptides orexin-A and orexin-B and the potent therapeutic inhibitor suvorexant. Here, using lipid-mediated crystallization and protein engineering with a novel fusion chimaera, we solved the structure of the human OX2R bound to suvorexant at 2.5 A resolution. The structure reveals how suvorexant adopts a pi-stacked horseshoe-like conformation and binds to the receptor deep in the orthosteric pocket, stabilizing a network of extracellular salt bridges and blocking transmembrane helix motions necessary for activation. Computational docking suggests how other classes of synthetic antagonists may interact with the receptor at a similar position in an analogous pi-stacked fashion. Elucidation of the molecular architecture of the human OX2R expands our understanding of peptidergic GPCR ligand recognition and will aid further efforts to modulate orexin signalling for therapeutic ends.
PDB ID: 4S0VDownload
MMDB ID: 126081
PDB Deposition Date: 2015/1/6
Updated in MMDB: 2017/09
Experimental Method:
x-ray diffraction
Resolution: 2.5  Å
Similar Structures:
Biological Unit for 4S0V: monomeric; determined by author and by software (PISA)
Molecular Components in 4S0V
Label Count Molecule
Protein (1 molecule)
1
Human Orexin Receptor Type 2 Fusion Protein to P. Abysii Glycogen Synthase(Gene symbol: HCRTR2)
Molecule annotation
Chemicals (2 molecules)
1
1
2
1
* Click molecule labels to explore molecular sequence information.

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