21CI
Crystal structure of human orexin type 2 receptor in complex with vornorexant
This is a non-PDB format compatible entry.
Summary for 21CI
| Entry DOI | 10.2210/pdb21ci/pdb |
| Descriptor | Orexin receptor type 2, vornorexant, SULFATE ION (3 entities in total) |
| Functional Keywords | ox2r, vornorexant, membrane protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 40201.50 |
| Authors | Mima, M.,Mishima-Tsumagari, C. (deposition date: 2025-12-08, release date: 2026-06-03, Last modification date: 2026-06-10) |
| Primary citation | Mima, M.,Mishima-Tsumagari, C.,Sakata-Sakuta, M.,Iwaoka, R.,Iwamoto, K. Structural insights into the binding mode of the hypnotic drug vornorexant to orexin receptors. Acta Crystallogr.,Sect.F, 82:201-207, 2026 Cited by PubMed Abstract: 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 (OXR) and a docking simulation of the drug with orexin type 1 receptor (OXR). The crystal structure of the OXR-vornorexant complex revealed a conserved U-shaped conformation stabilized by hydrophobic and hydrogen-bonding interactions, including key contacts with Asn324, His350 and Pro131. OXR-vornorexant docking simulations indicated a similar binding mode to OXR, 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. PubMed: 42059114DOI: 10.1107/S2053230X26003432 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.29 Å) |
Structure validation
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