Structure
Department of Biophysics, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan. Electronic address:
Published: March 2024
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 CH-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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http://dx.doi.org/10.1016/j.str.2023.12.008 | DOI Listing |
Protein Expr Purif
January 2025
VIB-VUB Center for Structural Biology, VIB, Pleinlaan 2, Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel (VUB), Pleinlaan 2, Brussels, Belgium. Electronic address:
Orexin receptors constitute a family of class A G-protein coupled receptors. There are two subtypes of orexin receptors, namely OX1R and OX2R. OX1R and OX2R are widely distributed in the central nervous system and are the targets for the peptide neurotransmitters orexin-A and orexin-B.
View Article and Find Full Text PDFBiotechnol Appl Biochem
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Department of Emergency Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
Dysfunction of the alveolar endothelial barrier plays a crucial role in the pathogenesis of septic acute lung injury (ALI). orexin B is a neuropeptide derived from orexin neurons in the lateral hypothalamus and has multiple biological functions. However, the physiological function of orexin B in sepsis is less reported.
View Article and Find Full Text PDFUnderstanding neural circuits involved in anesthesia is crucial for improving its safety and efficacy. Hypothalamic orexin neurons (LHA ), projecting broadly, are essential in regulating arousal and pain. However, the precise targets remain unclear.
View Article and Find Full Text PDFJ Ethnopharmacol
January 2025
College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China; Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China; Key Laboratory of Ginseng Efficacy Substance Base and Biological Mechanism Research, Ministry of Education, Changchun University of Chinese Medicine, Changchun, 130117, China. Electronic address:
Neuropeptides
December 2024
Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 311100, China. Electronic address:
Chronic pain induced by pathological insults to the sensorimotor system is a typical form of neuropathic pain (NP), and the underlying mechanism is complex. Currently, there are no successful therapeutic interventions for NP. Orexin B is a neuropeptide with a wide range of biological functions.
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