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At 0:00 am on February 4, 2021, Beijing time, the team of Professor Xia Ningshao of Xiamen University published an online publication titled "Cryo-EM Structures Reveal the Molecular Basis of Receptor-Initiated Coxsackievirus Uncoating" research paper.
This study clarified the interaction between Coxsackievirus B (CVB) and its highly dependent functional receptor Coxsackievirus and Adenovirus Receptor (CAR) and the fine features of the allosteric process , At the molecular level, revealed the mechanism and key sites of CAR-mediated high-efficiency decapsidation of CVB virus, and guided the discovery of a unique high-efficiency therapeutic antibody that can mimic the characteristics of receptors and induce the destabilization and disintegration of mature CVB virus particles.
.
This research can provide a key basis for the research of CVB vaccines and antiviral drugs, enrich the understanding of the interaction mechanism between the virus and the receptor, and provide an important reference and theoretical basis for the development of high-efficiency broad-spectrum antiviral drugs targeting the viral receptor binding domain .
Xiamen University postdoctoral fellow Xu Longfa, senior engineer Zheng Qingbing, doctoral student Zhu Rui, doctoral student Yin Zhichao, and Associate Professor Yu Hai are the co-first authors of the paper.
Professor Xia Ningshao, Professor Cheng Tong, and Professor Li Shaowei from Xiamen University and Professor Z.
Hong Zhou (Zhou Zhenghong) from the Institute of Nanosystems at the University of California, Los Angeles are the co-corresponding authors of the paper.
Coxsackie Group B virus (CVB) is an enterovirus pathogen that can cause a variety of serious diseases.
It can be transmitted through feces or mouth.
It is highly contagious and can infect infants, adolescents and adults.
It is widespread worldwide.There are 6 serotypes of CVB (CVB1～6), which can cause important diseases, including fever, hand, foot and mouth disease, diarrhea, encephalitis, meningitis, myocarditis, pancreatitis, acute flaccid paralysis, and even death.
Studies have found that CVB infection is closely related to viral pancreatitis and viral myocarditis, which have been increasing in incidence in recent years.
It is one of the main causes of type I diabetes and adolescent cardiogenic death, and has serious harm.
The importance and public health significance of CVB prevention and treatment has been highly valued.
However, there are currently no specific treatment drugs and preventive vaccines for CVB.
Related drugs are an important direction of current anti-enterovirus research.
At present, there is still a lack of clear understanding of the basic virology of CVB, especially the potential high-efficiency antiviral targets and the mechanism of effector molecules, which severely restricts the effective development of related research.
CAR is a functional cell receptor highly dependent on CVB infection, and is also called uncoating receptor.
CAR binding can induce the irreversible conformation of CVB mature virus particles and promote the release of nucleic acid, which plays a key role in CVB infection.
The CVB-CAR binding domain is an ideal target for discovering broad-spectrum antiviral targets.
However, there is still a lack of clear understanding of the precise characteristics and detailed mechanism of the interaction between CVB and CAR, and the precise information and targeted neutralizing antibodies for the potential and highly effective antiviral epitopes of the CAR binding domain of CVB have not been discovered and accurately identified.
It is a core scientific problem that needs to be solved urgently in the development of new vaccines or antiviral drugs.
The study constructed and analyzed the high-resolution structure of CVB virus particles and CAR receptor complexes, and obtained a series of near-atomic resolution structures representing different stages of virus infection under neutral pH conditions, including CVB1 mature particles (Mature virion), CAR-bound CVB1 precursor pre-A-particle, A-particle and empty particle under low temperature and physiological temperature, and capture CVB mature virus particles uncoated Many different intermediate states of the shell process and a series of fine conformational changes in the interaction domain of the CAR receptor.
Studies have shown that CAR binds to the "canyon" area around the five-fold axis formed by the capsid protein VP1 on the surface of the virus.
Compared with other known enterovirus uncapsid receptors, CAR binds deeper into the canyon groove.
In part, the VP1 hydrophobic "pocket" in the valley can be induced to collapse under physiologically neutral pH conditions, so that the lipid molecules (also known as "pocket factor") that maintain the stability of enterovirus particles in the hydrophobic pocket ) Release, thereby initiating the decapsidation process of mature virus particles, promoting the further transformation of the virus into the intermediate decapsidization state and hollow particles, and completing the complete decapsidation and genome release process of the virus.
The study explained the molecular mechanism of CAR binding driving CVB infection, revealed the precise interaction mode, domain characteristics and key amino acid sites between CVB and CAR, and found that the receptor binding domain can be used as a potential high-efficiency antiviral target.
Structural domains and key sites.
Based on the guidelines of the above findings, the study screened a unique and highly effective neutralizing antibody 5F5 that can mimic the receptor action characteristics and induce the destabilization and disintegration of CVB mature virus particles.
Studies have found that 5F5 can block or compete for the interaction between CAR and CVB through steric hindrance.
It can not only simulate the interaction between the receptor and virus particles, but also induce the key target VP2 EF-loop of the CAR binding domain of the receptor.
The conformational change of the virus destroys the stability of the virus capsid, and finally leads to the lysis of the mature virus particle to exert an efficient neutralization effect. This is what Professor Xia Ningshao’s team has done in recent years in "Nature Communications" (Nature Communications, 2017), "Science Advances" (Science Advances, 2018), "Nature Microbiology" (Nature Microbiology, 2019) and "Cell• Another important research result after the publication of research papers on the important enterovirus pathogens CVA6, CVA10, EVD68 and CVA16 in "Cell Host & Microbe" (Cell Host & Microbe, 2020), enriches the mechanism of enterovirus infection and the interaction with the receptor The basic theory of the discovery of the precise information of the key antiviral target of the receptor binding domain and the effector antibody molecule is of great value and significance for the rational design and application development of new vaccine immunogens and antiviral drugs.
Related paper information: https://doi.
org/10.
1016/j.
chom.
2021.
01.
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This study clarified the interaction between Coxsackievirus B (CVB) and its highly dependent functional receptor Coxsackievirus and Adenovirus Receptor (CAR) and the fine features of the allosteric process , At the molecular level, revealed the mechanism and key sites of CAR-mediated high-efficiency decapsidation of CVB virus, and guided the discovery of a unique high-efficiency therapeutic antibody that can mimic the characteristics of receptors and induce the destabilization and disintegration of mature CVB virus particles.
.
This research can provide a key basis for the research of CVB vaccines and antiviral drugs, enrich the understanding of the interaction mechanism between the virus and the receptor, and provide an important reference and theoretical basis for the development of high-efficiency broad-spectrum antiviral drugs targeting the viral receptor binding domain .
Xiamen University postdoctoral fellow Xu Longfa, senior engineer Zheng Qingbing, doctoral student Zhu Rui, doctoral student Yin Zhichao, and Associate Professor Yu Hai are the co-first authors of the paper.
Professor Xia Ningshao, Professor Cheng Tong, and Professor Li Shaowei from Xiamen University and Professor Z.
Hong Zhou (Zhou Zhenghong) from the Institute of Nanosystems at the University of California, Los Angeles are the co-corresponding authors of the paper.
Coxsackie Group B virus (CVB) is an enterovirus pathogen that can cause a variety of serious diseases.
It can be transmitted through feces or mouth.
It is highly contagious and can infect infants, adolescents and adults.
It is widespread worldwide.There are 6 serotypes of CVB (CVB1～6), which can cause important diseases, including fever, hand, foot and mouth disease, diarrhea, encephalitis, meningitis, myocarditis, pancreatitis, acute flaccid paralysis, and even death.
Studies have found that CVB infection is closely related to viral pancreatitis and viral myocarditis, which have been increasing in incidence in recent years.
It is one of the main causes of type I diabetes and adolescent cardiogenic death, and has serious harm.
The importance and public health significance of CVB prevention and treatment has been highly valued.
However, there are currently no specific treatment drugs and preventive vaccines for CVB.
Related drugs are an important direction of current anti-enterovirus research.
At present, there is still a lack of clear understanding of the basic virology of CVB, especially the potential high-efficiency antiviral targets and the mechanism of effector molecules, which severely restricts the effective development of related research.
CAR is a functional cell receptor highly dependent on CVB infection, and is also called uncoating receptor.
CAR binding can induce the irreversible conformation of CVB mature virus particles and promote the release of nucleic acid, which plays a key role in CVB infection.
The CVB-CAR binding domain is an ideal target for discovering broad-spectrum antiviral targets.
However, there is still a lack of clear understanding of the precise characteristics and detailed mechanism of the interaction between CVB and CAR, and the precise information and targeted neutralizing antibodies for the potential and highly effective antiviral epitopes of the CAR binding domain of CVB have not been discovered and accurately identified.
It is a core scientific problem that needs to be solved urgently in the development of new vaccines or antiviral drugs.
The study constructed and analyzed the high-resolution structure of CVB virus particles and CAR receptor complexes, and obtained a series of near-atomic resolution structures representing different stages of virus infection under neutral pH conditions, including CVB1 mature particles (Mature virion), CAR-bound CVB1 precursor pre-A-particle, A-particle and empty particle under low temperature and physiological temperature, and capture CVB mature virus particles uncoated Many different intermediate states of the shell process and a series of fine conformational changes in the interaction domain of the CAR receptor.
Studies have shown that CAR binds to the "canyon" area around the five-fold axis formed by the capsid protein VP1 on the surface of the virus.
Compared with other known enterovirus uncapsid receptors, CAR binds deeper into the canyon groove.
In part, the VP1 hydrophobic "pocket" in the valley can be induced to collapse under physiologically neutral pH conditions, so that the lipid molecules (also known as "pocket factor") that maintain the stability of enterovirus particles in the hydrophobic pocket ) Release, thereby initiating the decapsidation process of mature virus particles, promoting the further transformation of the virus into the intermediate decapsidization state and hollow particles, and completing the complete decapsidation and genome release process of the virus.
The study explained the molecular mechanism of CAR binding driving CVB infection, revealed the precise interaction mode, domain characteristics and key amino acid sites between CVB and CAR, and found that the receptor binding domain can be used as a potential high-efficiency antiviral target.
Structural domains and key sites.
Based on the guidelines of the above findings, the study screened a unique and highly effective neutralizing antibody 5F5 that can mimic the receptor action characteristics and induce the destabilization and disintegration of CVB mature virus particles.
Studies have found that 5F5 can block or compete for the interaction between CAR and CVB through steric hindrance.
It can not only simulate the interaction between the receptor and virus particles, but also induce the key target VP2 EF-loop of the CAR binding domain of the receptor.
The conformational change of the virus destroys the stability of the virus capsid, and finally leads to the lysis of the mature virus particle to exert an efficient neutralization effect. This is what Professor Xia Ningshao’s team has done in recent years in "Nature Communications" (Nature Communications, 2017), "Science Advances" (Science Advances, 2018), "Nature Microbiology" (Nature Microbiology, 2019) and "Cell• Another important research result after the publication of research papers on the important enterovirus pathogens CVA6, CVA10, EVD68 and CVA16 in "Cell Host & Microbe" (Cell Host & Microbe, 2020), enriches the mechanism of enterovirus infection and the interaction with the receptor The basic theory of the discovery of the precise information of the key antiviral target of the receptor binding domain and the effector antibody molecule is of great value and significance for the rational design and application development of new vaccine immunogens and antiviral drugs.
Related paper information: https://doi.
org/10.
1016/j.
chom.
2021.
01.
001 2020 Hot Article Selection 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 fatal changes do not occur in the brain, but in the intestines.
.
.
9.
The ultra-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.
.
.
