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Crystal structure of the human OX^sub 2^ orexin receptor bound to the insomnia drug suvorexant
Ist Teil von
Nature (London), 2015-03, Vol.519 (7542), p.247
Ort / Verlag
London: Nature Publishing Group
Erscheinungsjahr
2015
Link zum Volltext
Quelle
Psychology & Behavioral Sciences Collection
Beschreibungen/Notizen
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 humans1. Defects in orexin signalling are responsible for the human diseases of narcolepsy and cataplexy; inhibition of orexin receptors is an effective therapy for insomnia2. The human OX^sub 2^ receptor (OX^sub 2^R) belongs to the β branch of the rhodopsin family of GPCRs3, and can bind to diverse compounds including the native agonist peptides orexin-A and orexin-B and the potent therapeutic inhibitor suvorexant4. Here, using lipid-mediated crystallization and protein engineering with a novel fusion chimaera, we solved the structure of the human OX^sub 2^R bound to suvorexant at 2.5 Å resolution. The structure reveals how suvorexant adopts a π-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 π-stacked fashion. Elucidation of the molecular architecture of the human OX^sub 2^R expands our understanding of peptidergic GPCR ligand recognition and will aid further efforts to modulate orexin signalling for therapeutic ends.