4s0v

Crystal structure of the human OX2 orexin receptor bound to the insomnia drug Suvorexant

spinqualitylabelsall models 4s0v, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4s0v is a 1 chain structure with sequence from Homo sapiens and Pyrococcus abyssi GE5. This structure supersedes the now removed PDB entry 4rnb. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.5Å Ligands: OLA, SUV Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q9V2J8_PYRAB OX2R_HUMAN Nonselective, high-affinity receptor for both orexin-A and orexin-B neuropeptides. Publication Abstract from PubMed 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. Crystal structure of the human OX orexin receptor bound to the insomnia drug suvorexant.,Yin J, Mobarec JC, Kolb P, Rosenbaum DM Nature. 2014 Dec 22. doi: 10.1038/nature14035. PMID:25533960 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Orexin and Orexin receptor

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