核磁共振波谱
化学
受体
光谱学
立体化学
生物化学
物理
量子力学
作者
Kiichi Imamura,Ken‐ichi Akagi,Yohei Miyanoiri,Hirokazu Tsujimoto,Takatsugu Hirokawa,Hiroshi Ashida,Kaori Murakami,Asuka Inoue,Ryoji Suno,Takahisa Ikegami,Naotaka Sekiyama,So Iwata,Takuya Kobayashi,Hidehito Tochio
出处
期刊:Structure
[Elsevier]
日期:2024-03-01
卷期号:32 (3): 352-361.e5
标识
DOI:10.1016/j.str.2023.12.008
摘要
Summary
Orexin neuropeptides have many physiological roles in the sleep-wake cycle, feeding behavior, reward demands, and stress responses by activating cognitive receptors, the orexin receptors (OX1R and OX2R), distributed in the brain. There are only subtle differences between OX1R and OX2R in the orthosteric site, which has hindered the rational development of subtype-selective antagonists. In this study, we utilized solution-state NMR to capture the structural plasticity of OX2R labeled with 13CH3-ε-methionine in complex with antagonists. Mutations in the orthosteric site allosterically affected the intracellular tip of TM6. Ligand exchange experiments with the subtype-selective EMPA and the nonselective suvorexant identified three methionine residues that were substantially perturbed. The NMR spectra suggested that the suvorexant-bound state exhibited more structural plasticity than the EMPA-bound state, which has not been foreseen from the close similarity of their crystal structures, providing insights into dynamic features to be considered in understanding the ligand recognition mode.
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