Cell Res | Shanghai Institute of Medicine Xu Huaqiang/Jiang Yi reveals the selective action mechanism of anti-migraine drugs

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iNature migraine is a neurological disease with a wide range of effects, affecting more than one billion people worldwide, causing a huge socioeconomic burden
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According to statistics, in Europe, migraine causes more than 27 billion euros of economic losses every year, and about 1 in 11 adults in China suffers from migraine
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In addition, migraine will be accompanied by a series of diseases including depression, anxiety, epilepsy, obesity and other chronic pain, which will bring a heavy burden to patients and their families
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On July 8, 2021, Xu Huaqiang and Jiang Yi from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences published an online communication titled "Structural basis for recognition of anti-migraine drug lasmiditan by the serotonin receptor 5-HT1F–G protein complex" in Cell Research.
The research paper reported on the cryo-EM structure of the 5-HT1F-Gi complex combined with the highly selective anti-migraine drug lasmiditan
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This structure reveals the binding mode of lasmiditan in 5-HT1F
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 The comparison of the structure of this study with the previously reported structure of 5-HT1 provides a basis for the selectivity of lasmiditan to 5-HT1F
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The determination of selectivity is mainly due to the interaction between the trifluorophenyl group of lasmiditan and the specific EBP of 5-HT1F
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In addition, the structure of this study reveals the conserved mechanism of 5-HT1F activation and the unique G protein-coupled conformation of other 5-HT1-G protein structures
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These results provide a reasonable template for the design of a new generation of anti-migraine drugs that selectively target 5-HT1F, thereby avoiding the major shortcomings of cardiovascular side effects associated with triptan anti-migraine drugs
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Serotonin 5-HT1 receptor subtypes, including 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F, are G protein-coupled receptors (GPCR), which are used for endogenous neurotransmitters Serotonin is responsive and preferentially couples to the Gi/o family of G protein
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Drugs that target the 5-HT1 receptor are used to treat migraine, depression, and schizophrenia
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 The clinical use of traditional anti-migraine drugs, triptans, can cause side effects caused by therapeutic vasoconstriction when targeted
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The demand for new anti-migraine drugs without vasoconstriction has led to the development of lasmiditan, a highly selective 5-HT1F receptor agonist with minimal targeted side effects
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Migraine is one of the most common diseases in the world, and importantly, it is the main cause of reduced work efficiency
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Selective 5-HT1B/D agonists triptans are currently used for the first-line acute treatment of moderate to severe migraine
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Triptans mainly bind to 5-HT1B/D receptors in cerebral blood vessels, causing vasoconstriction
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Unfortunately, a large proportion of patients are not satisfied with current acute migraine treatment, because 5-HT1B/D receptors also exist on coronary and limb arteries, and triptans may cause cardiovascular disease or not.
Patients with the disease have acute coronary syndromes
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Electron microscopic structure of 5-HT1F receptor-Gi protein-lamitetan complex
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Receptor: green; Gαi subunit: yellow; Gβ subunit: blue; Gγ subunit: purple; Lamitan: pink
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Lasmiditan is a potent selective 5-HT1F receptor agonist and has recently been approved for the treatment of acute migraine
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Lasmiditan has no vasoconstrictor effect and may be a safer and more effective option for patients and patients refractory to triptans
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Lasmiditan has a pyridyl-piperidine scaffold, and its structure is different from the indole derivatives of triptans
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In addition, lasmiditan can penetrate the blood-brain barrier and act on receptors in the brain, thereby enhancing its effect on receptor sites in the central nervous system (CNS)
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How the anti-migraine drug lamitetan (pink) interacts with the 5-HT1F receptor (green)
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In order to better understand the structural basis of the selectivity and activation of lasmiditan for 5-HT1F, this study determined the structure of the complex of 5-HT1F with lasmiditan and Gi1 at a resolution of 3.
4 Å through single-particle cryo-electron microscopy
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This structure reveals the mechanism of 5-HT1F selective activation and provides a template for the rational design of anti-migraine drugs
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Xu Huaqiang's research group has been committed to the structure and function of serotonin family receptors for a long time, and has achieved a series of important systematic results
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The research team published the first 5-HT1B receptor crystal structure on Science in 2013 [1]; in 2018, it published the first antagonistic 5-HT1B receptor structure [2] on Cell Discovery; in 2021 The cryo-EM structure of three different subtypes of 5-HT receptors and G protein complexes was published on Nature in March 2003, and for the first time revealed the lipid regulation, constitutive activation, and anti-schizophrenia of 5-HT receptors.
The mechanism of action of the antidepressant drug aripiprazole [3]
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The team's achievements in the mechanism of action of 5-HT1F receptors and anti-migraine drugs have further achieved an important breakthrough in the field of 5-HT receptor system research
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Shanghai Institute of Materia Medica and Shanghai University of Science and Technology jointly cultivated PhD student Huang Sijie, Shanghai Institute of Materia Medica, PhD student Xu Peiyu, and research assistant Tan Yangxia as the co-first authors of the article; Shanghai Institute of Materia Medica Researcher Xu Huaqiang and Researcher Jiang Yi are the co-corresponding authors of the article
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The research was funded by the National Key Research and Development Program, the Strategic Leading Science and Technology Project of the Chinese Academy of Sciences, the Shanghai Municipal Science and Technology Major Project, the National Natural Science Foundation of China, and the National Science and Technology Major Project
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Reference 1, Wang, C.
et al.
Structural Basis for Molecular Recognition at Serotonin Receptors.
Science 340, 610-614, doi:10.
1126/science.
1232807 (2013).
2, Yin, W.
et al.
Crystal structure of the human 5-HT1B serotonin receptor bound to an inverse agonist.
Cell Discov 4, 12, doi:10.
1038/s41421-018-0009-2 (2018).
3, Xu, P.
et al.
Structural insights into the lipid and ligand regulation of serotonin receptors.
Nature 592, 469-473, doi:10.
1038/s41586-021-03376-8 (2021).
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