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Migraine is a neurological disease with a very wide range of effects, affecting more than 1 billion people worldwide, causing a huge socioeconomic burden
.
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
.
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
.
Serotonin (5-HT) family receptors are important targets for central nervous system diseases such as migraine, depression, and schizophrenia
.
Among them, the three subtypes of 5-HT1B, 5-HT1D and 5-HT1F are closely related to the treatment of migraine
.
For many years, triptans, which are agonists targeting 5-HT1B/1D, have been widely used in the treatment of migraine
.
However, the vasoconstrictor activity of these drugs brings certain treatment risks to patients with a history of coronary heart disease, cerebrovascular disease or hypertension
.
In 2019, the US FDA approved a new type of acute migraine treatment drug-Lasmiditan (Lasmiditan) that targets 5-HT1F with high selectivity
.
Lamitriptan can effectively avoid the cardiovascular side effects of triptan drugs, but the mechanism of its selective targeting of 5-HT1F receptors is still unclear
.
As a promising anti-migraine target, 5-HT1F is of great significance to the study of its structure, function and the mechanism of action of selective drugs
.
Recently, Xu Huaqiang's research group at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences used cryo-electron microscopy to analyze the complex structure of 5-HT1F receptor binding G protein and the anti-migraine drug lamitetan for the first time, revealing the selectivity of lamitetan Bind to the structural basis of 5-HT1F receptor
.
The result is titled "Structural basis for recognition of anti-migraine drug lasmiditan by the serotonin receptor 5-HT1F–G protein complex" and will be published online in Cell Research on July 8, 2021
.
Electron microscopic structure of 5-HT1F receptor-Gi protein-lamitetan complex
.
Receptor: green; Gαi subunit: yellow; Gβ subunit: blue; Gγ subunit: purple; Lamitan: pink
.
How the anti-migraine drug lamitetan (pink) interacts with the 5-HT1F receptor (green)
.
5-HT1F is a member of the 5-HT1 subfamily, but it is relatively different from other subtypes of this subfamily in terms of homology and ligand activation effects, which also makes 5-HT1F a potential selective anti-migraine Target
.
After purifying, freezing samples and data processing conditions, the research team broke through the technical bottleneck of low expression of 5-HT1F receptor-G protein complex and unstable complex assembly, and finally obtained a high-quality complex structure
.
Compared with other 5-HT subtype receptors, the structure near the extracellular region of the 5-HT1F receptor has a significant conformational change, which is also the structural basis for the drug lamitetan to bind the 5-HT1F receptor with high selectivity
.
ab.
Electron microscope density map (a) and atomic model (b) of the 5-HT1F-Gi-lamitetan complex; c.
Schematic diagram of the binding pocket of lamitetan; d.
The interaction pattern of the body; e.
G protein recruitment experiments show that lamitetan is highly selective for 5-HT1F receptor
.
Full text link https:// 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 systematic important Results
.
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]
.
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
.
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
.
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
.
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).
Hot Article Selection in 2020 1.
Cups! A full paper cup of hot coffee, full of plastic particles.
.
.
2.
Scientists from the United States, Britain and Australia “Natural Medicine” further prove that the new coronavirus is a natural evolution product, or has two origins.
.
.
3.
NEJM: Intermittent fasting is right The impact of health, aging and disease 4.
Heal insomnia within one year! The study found that: to improve sleep, you may only need a heavy blanket.
5.
New Harvard study: Only 12 minutes of vigorous exercise can bring huge metabolic benefits to health.
6.
The first human intervention experiment: in nature.
"Feeling and rolling" for 28 days is enough to improve immunity.
7.
Junk food is "real rubbish"! It takes away telomere length and makes people grow old faster! 8.
Cell puzzle: you can really die if you don't sleep! But the lethal changes do not occur in the brain, but in the intestines.
.
.
9.
The super large-scale study of "Nature Communications": The level of iron in the blood is the key to health and aging! 10.
Unbelievable! Scientists reversed the "permanent" brain damage in animals overnight, and restored the old brain to a young state.
.
.
.
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
.
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
.
Serotonin (5-HT) family receptors are important targets for central nervous system diseases such as migraine, depression, and schizophrenia
.
Among them, the three subtypes of 5-HT1B, 5-HT1D and 5-HT1F are closely related to the treatment of migraine
.
For many years, triptans, which are agonists targeting 5-HT1B/1D, have been widely used in the treatment of migraine
.
However, the vasoconstrictor activity of these drugs brings certain treatment risks to patients with a history of coronary heart disease, cerebrovascular disease or hypertension
.
In 2019, the US FDA approved a new type of acute migraine treatment drug-Lasmiditan (Lasmiditan) that targets 5-HT1F with high selectivity
.
Lamitriptan can effectively avoid the cardiovascular side effects of triptan drugs, but the mechanism of its selective targeting of 5-HT1F receptors is still unclear
.
As a promising anti-migraine target, 5-HT1F is of great significance to the study of its structure, function and the mechanism of action of selective drugs
.
Recently, Xu Huaqiang's research group at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences used cryo-electron microscopy to analyze the complex structure of 5-HT1F receptor binding G protein and the anti-migraine drug lamitetan for the first time, revealing the selectivity of lamitetan Bind to the structural basis of 5-HT1F receptor
.
The result is titled "Structural basis for recognition of anti-migraine drug lasmiditan by the serotonin receptor 5-HT1F–G protein complex" and will be published online in Cell Research on July 8, 2021
.
Electron microscopic structure of 5-HT1F receptor-Gi protein-lamitetan complex
.
Receptor: green; Gαi subunit: yellow; Gβ subunit: blue; Gγ subunit: purple; Lamitan: pink
.
How the anti-migraine drug lamitetan (pink) interacts with the 5-HT1F receptor (green)
.
5-HT1F is a member of the 5-HT1 subfamily, but it is relatively different from other subtypes of this subfamily in terms of homology and ligand activation effects, which also makes 5-HT1F a potential selective anti-migraine Target
.
After purifying, freezing samples and data processing conditions, the research team broke through the technical bottleneck of low expression of 5-HT1F receptor-G protein complex and unstable complex assembly, and finally obtained a high-quality complex structure
.
Compared with other 5-HT subtype receptors, the structure near the extracellular region of the 5-HT1F receptor has a significant conformational change, which is also the structural basis for the drug lamitetan to bind the 5-HT1F receptor with high selectivity
.
ab.
Electron microscope density map (a) and atomic model (b) of the 5-HT1F-Gi-lamitetan complex; c.
Schematic diagram of the binding pocket of lamitetan; d.
The interaction pattern of the body; e.
G protein recruitment experiments show that lamitetan is highly selective for 5-HT1F receptor
.
Full text link https:// 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 systematic important Results
.
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]
.
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
.
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
.
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
.
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).
Hot Article Selection in 2020 1.
Cups! A full paper cup of hot coffee, full of plastic particles.
.
.
2.
Scientists from the United States, Britain and Australia “Natural Medicine” further prove that the new coronavirus is a natural evolution product, or has two origins.
.
.
3.
NEJM: Intermittent fasting is right The impact of health, aging and disease 4.
Heal insomnia within one year! The study found that: to improve sleep, you may only need a heavy blanket.
5.
New Harvard study: Only 12 minutes of vigorous exercise can bring huge metabolic benefits to health.
6.
The first human intervention experiment: in nature.
"Feeling and rolling" for 28 days is enough to improve immunity.
7.
Junk food is "real rubbish"! It takes away telomere length and makes people grow old faster! 8.
Cell puzzle: you can really die if you don't sleep! But the lethal changes do not occur in the brain, but in the intestines.
.
.
9.
The super large-scale study of "Nature Communications": The level of iron in the blood is the key to health and aging! 10.
Unbelievable! Scientists reversed the "permanent" brain damage in animals overnight, and restored the old brain to a young state.
.
.
