7XRR

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

7XRR の概要

• エントリーDOI: 10.2210/pdb7xrr/pdb
• 分子名称: 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)
• 機能のキーワード: gpcr, insomnia drug, membrane protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 39972.32

構造登録者

Asada, H.,Im, D.,Iwata, S. (登録日: 2022-05-11, 公開日: 2022-11-23, 最終更新日: 2024-11-06)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.89 Å)