7XRR

Crystal structure of the human OX2R bound to the insomnia drug lemborexant.

Summary for 7XRR

• Entry DOI: 10.2210/pdb7xrr/pdb
• Descriptor: Orexin receptor type 2, (1~{R},2~{S})-2-[(2,4-dimethylpyrimidin-5-yl)oxymethyl]-~{N}-(5-fluoranylpyridin-2-yl)-2-(3-fluorophenyl)cyclopropane-1-carboxamide (2 entities in total)
• Functional Keywords: gpcr, insomnia drug, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 39972.32

Authors

Asada, H.,Im, D.,Iwata, S. (deposition date: 2022-05-11, release date: 2022-11-23, Last modification date: 2024-11-06)

Primary citation

Asada, H.,Im, D.,Hotta, Y.,Yasuda, S.,Murata, T.,Suno, R.,Iwata, S.
Molecular basis for anti-insomnia drug design from structure of lemborexant-bound orexin 2 receptor.
Structure, 30:1582-1589.e4, 2022

PubMed Abstract: Orexin receptors are a family of G protein-coupled receptors that consist of two subtypes: orexin-1 receptors (OX1Rs) and OX2Rs. They are expressed throughout the central nervous system and are involved in regulating the sleep-wake cycle. The development of antagonists to orexin receptors has become important in drug discovery because modulation of these receptors can lead to novel treatments for diseases related to the regulation of sleep and wakefulness, such as insomnia. In this study, we determined that the structure of OX2R bound to lemborexant, a dual orexin receptor antagonist (DORA), at 2.89 Å resolution. Comparisons of kinetic and dynamic properties of DORAs based on structures and simulations suggest that the enthalpy of molecular binding to receptors and the entropy derived from intramolecular structure can be separately controlled. These results complement existing structural information and allow us to discuss the usefulness of pharmacophore models and target selectivity to OXRs.

PubMed: 36417909
DOI: 10.1016/j.str.2022.11.001

Experimental method

X-RAY DIFFRACTION (2.89 Å)