21ci

Crystal structure of human orexin type 2 receptor in complex with vornorexant

spinqualitylabelsall models 21ci, resolution 3.29Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 21ci is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.29Å Ligands: A1MCY, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function OX2R_HUMAN Nonselective, high-affinity receptor for both orexin-A and orexin-B neuropeptides. Publication Abstract from PubMed Insomnia is a widespread sleep disorder that significantly impairs quality of life and imposes a societal burden. Although benzodiazepines and Z-drugs are commonly used for treating insomnia, these drugs often have side effects, such as excessive muscle relaxation and dependency. The orexin signaling pathway has emerged as a promising therapeutic target for insomnia, with dual orexin receptor antagonists (DORAs) offering an alternative approach to treatment. To reduce the potential of these drugs for next-day residual effects, we developed vornorexant, a novel DORA with a high receptor affinity and a short elimination half-life. In this study, we investigated the molecular interactions of this drug with human orexin receptors through crystal structure analysis of its binding to orexin type 2 receptor (OX(2)R) and a docking simulation of the drug with orexin type 1 receptor (OX(1)R). The crystal structure of the OX(2)R-vornorexant complex revealed a conserved U-shaped conformation stabilized by hydrophobic and hydrogen-bonding interactions, including key contacts with Asn324, His350 and Pro131. OX(1)R-vornorexant docking simulations indicated a similar binding mode to OX(1)R, with no steric hindrance observed, supporting a balanced dual antagonism. These results provide a structural basis for the high-affinity dual antagonism of vornorexant and offer insights for the design of orexin receptor antagonists. Structural insights into the binding mode of the hypnotic drug vornorexant to orexin receptors.,Mima M, Mishima-Tsumagari C, Sakata-Sakuta M, Iwaoka R, Iwamoto K Acta Crystallogr F Struct Biol Commun. 2026 Jun 1;82(Pt 6):201-207. doi: , 10.1107/S2053230X26003432. Epub 2026 Apr 30. PMID:42059114 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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