Currently, about 70 to 100 million people worldwide suffer from early-stage Alzheimer's disease, and 1 billion people are suffering from mental disorders
On June 16, "Nature" published two "back-to-back" research results online
These two studies by the Chinese Academy of Sciences Shanghai Institute of Materia Medica researcher Wu Beili study groups, study groups Qiang, Wang Mingwei research group, study group Hong Liu, Chinese Academy of Sciences researcher at the Institute of Biophysics Fei Sun Research Group and Huazhong University of Science Professor Liu Jianfeng Group research collaboration
Chinese Academy of Sciences New therapeutic target
New therapeutic target "Scientific American" once published an article that the failure rate of drug development for Alzheimer's disease is as high as 99.
mGlu belongs to the C-type GPCR family and is one of the most important neurotransmitter receptors in the human body
However, no drugs targeting this type of receptor have been successfully marketed so far
"Different from other types of GPCRs, class C GPCRs such as mGlu have a unique activation mechanism, and the receptor must form a homologous or heterodimer to
However, the regulation mechanism of different types of dimerization on receptor activity and how this type of receptor activates intracellular effectors such as G protein has been unclear for a long time
In order to assist the development of drugs for neuropsychiatric diseases and to explore the mechanism of the interaction between mGlu2 and potential drug molecules, in 2015, Beili Wu's team began to target mGlu for research
With the growth of the research team and the accumulation of research experience, the Wu Beili team gradually deepened the research content, from the initial supplementary drug development to the simultaneous and systematic solution of scientific questions that need to be answered
"The research on the structure of GPCRs is inherently difficult.
Analyze the three-dimensional structure
Analyze the three-dimensional structure Previous studies have shown that class C GPCR dimers regulate the function of receptors by regulating the relative conformation between the two subunits
Studies have shown that, similar to the previously determined structure of mGlu5, the inactive state structure of mGlu7 presents a completely open conformation, with the transmembrane domains of the two subunits farther apart without direct contact
The difference is that the two transmembrane domains in the mGlu2 dimer are close to each other and form a close interaction through the respective fourth transmembrane helix
In this regard, the researchers used amino acid mutations and cell signal transduction experiments to further confirm that this dimer interface in mGlu2 is unique to the receptor subtype and plays an important role in stabilizing the inactive state of the receptor
"We hope to fully analyze the mGlu in different active states, especially the active state
.
" To this end, Beili Wu's team also conducted research on the complexes of mGlu2 and agonists
.
Based on the structure of mGlu2 in the non-activated state, activated intermediate state and fully activated state, the research team fully explained the fine conformational changes of mGlu during the entire activation process for the first time, providing key information for in-depth understanding of the activation mechanism of class C GPCRs
.
In addition, the research team also analyzed the complex structure of the mGlu2 transmembrane domain combined with two negative allosteric modulators, and carried out systematic functional studies
.
Team "back-to-back" operations
Team "back-to-back" operations In fact, domestic and foreign research on class C GPCRs has been for some time.
According to Wu Beili, the reason why the dimerization and functional regulation mechanism of class C GPCRs can be revealed this time is due to the development of cryo-electron microscopy technology on the one hand, and the other On the one hand is the large team fighting "back-to-back"
.
Although with the support of cryo-electron microscopy technology, research is still very difficult
.
"We screened out mGlu2 from the existing 8 types of mGlu, but the cryo-electron microscopy technology at that time was not very suitable for analyzing the structure of mGlu2, so we used the X-ray crystal diffraction method to determine the protein, but it needs to be very stable.
Protein samples
.
" Wu Beili said
.
Due to lack of experience, the research team initially crossed the river by feeling the stones
.
After more than two years of exploration, they finally obtained a high-quality protein sample
.
However, the challenge has just begun
.
"Although you can start to use cryo-electron microscopy after getting a good protein sample, due to lack of experience and the strong conformational flexibility of mGlu2, the whole work is full of challenges
.
" Wu Beili told China Science Daily
.
With the further in-depth research, just when everyone thought that a very good protein sample had been obtained, the research team fell into the dilemma of data collection
.
"Because of the strong conformational flexibility of class C GPCRs, it is difficult to collect high-resolution data.
It is necessary to collect massive amounts of data to select the best data
.
" Wu Beili said
.
In addition to the teachers, many doctoral students in the research group have focused their energy on this research.
Seeing that they have not made major breakthroughs after years of hard work, the students were also distressed for a time in the face of pressure from graduation and other aspects
.
To this end, the teachers of the research group encourage students to set up small teams to help each other to encourage and learn from each other
.
Finally, after more than a year of exploration, six electron microscope structures were analyzed.
“Each structure has a large amount of data behind it.
It may take 3 to 4 days to collect at least, and 7 to 8 days to collect at most
.
” Wu Beili Said that in order to race against time to organize the data, these students spent their 30th year in the laboratory
.
In Wu Beili's view, breakthroughs in these issues have also benefited from the research results of the large team.
"Many scientific issues are analogous.
With the accumulation of the results of the entire platform, many problems will be solved
.
"
"MGlu still has many scientific problems to be solved.
In the future, we hope to assist drug development while answering scientific questions.
This is one of our main directions
.
" Wu Beili said
.
(Source: Tian Ruiying, Chinese Science News)
Related paper information:
https://doi.
org/10.
1038/s41586-021-03641-w
https://doi.
org/10.
1038/s41586-021-03641-w https://doi.
org/10.
1038/s41586-021-03495-2
https://doi.
org/10.
1038/s41586-021-03495-2
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