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Non-canonical G q activation by orexin receptor type 2 and lemborexant observed in microsecond molecular dynamics simulations
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Non-canonical G q activation by orexin receptor type 2 and lemborexant observed in microsecond molecular dynamics simulations
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Journal Article
Non-canonical G q activation by orexin receptor type 2 and lemborexant observed in microsecond molecular dynamics simulations
2025
Overview
Orexins are hypothalamic neuropeptides primarily involved in regulating the sleep/wakefulness cycle and circadian rhythm. They bind to the orexin receptor type 1 (OX
) and type 2 (OX
), well-known drug targets in the treatment of sleep disorders, that have recently been shown to play a significant role in different cancers. Lemborexant is one of a few orexin receptor antagonists that have been approved for the treatment of insomnia. Despite being classified as an antagonist, lemborexant may display agonist-like behavior in the non-canonical signaling pathway of the orexin receptors, as confirmed recently in cancer cell models. Here, we generated a model of OX
in complex with the full-length G
protein and used it in the molecular dynamics (MD) study. We compared the impact of lemborexant and the OX
-selective, potent agonist compound 1 on OX
activation and subsequent guanosine diphosphate (GDP) to guanosine triphosphate (GTP) exchange in the Gα
subunit. These 2 µs MD simulations showed that both ligands evoke similar, activation-like conformational changes in OX
and explained the observed lemborexant-mediated apoptosis of cancer cells. In addition, MD simulations of the active-state OX
-G
complexes allowed us to uncover a sequence of micro- and macroscale events during the activation of G
and to detect important micro- and macroswitches in the Gα subunit.
Subject
GTP-Binding Protein alpha Subunits, Gq-G11 - chemistry
/ GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism
/ Humans
/ Molecular Dynamics Simulation
/ Orexin Receptor Antagonists - chemistry
/ Orexin Receptor Antagonists - pharmacology
/ Orexin Receptors - chemistry
