​Led by Wu Beili/Zhao Qiang, two "Nature" on the same day reveal the structure of key neurotransmitter receptors

▎Editor of WuXi AppTec's content team Today, the top academic journal "Nature" published two important structural biology papers back to back, revealing the structure of a key neurotransmitter receptor
.

Researcher Wu Beili and researcher Zhao Qiang of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences are both corresponding authors of the two papers, and a number of researchers from the Shanghai Institute of Materia Medica and Guangzhou Biological Island Laboratory participated in the study as corresponding authors
.

▲ Researcher Wu Beili (left) and researcher Zhao Qiang (right) are the corresponding authors of these two papers (photo source: Shanghai Institute of Materia Medica, Chinese Academy of Sciences).
These two studies are important for understanding metabotropic glutamate receptors (mGlus).
) Is of great significance
.

We know that glutamate is the most fundamental excitatory neurotransmitter in the mammalian central nervous system, and it plays an important role in memory, neurodevelopment, and synaptic plasticity
.

Glutamate receptors can be divided into two categories, namely ionotropic glutamate receptors and metabotropic glutamate receptors, the latter through a series of cell signaling pathways (such as G protein coupled signaling pathways), which can affect To the effect of glutamate on synaptic transmission
.

▲The first paper comes from the research group of Wu Beili, Zhao Qiang, and Wang Mingwei (picture source: screenshot from the official website of Nature).
In the first paper, the scientists pointed out that previous studies have shown that the metabotropic glutamate receptor In the aggregate, only one receptor subunit is responsible for coupling with the G protein during receptor activation
.

In order to understand the underlying mechanism, the team used cryo-electron microscopy technology to obtain two structures formed by the combination of human mGlu2 and mGlu4 with the heterotrimeric Gi protein
.

Through structural analysis, the researchers found that the binding site of metabotropic glutamate receptor and G protein is significantly different from the corresponding site where other G protein-coupled receptors bind to G protein
.

In addition, in the receptor transmembrane domains of these two structures, researchers have also observed asymmetric dimerization
.

Through functional analysis, the researchers confirmed that this asymmetric dimer phenomenon is essential for receptor activation, and may be the molecular basis for asymmetric signaling of metabotropic glutamate receptors
.

▲The second paper was jointly brought by Zhao Qiang, Wu Beili, Sun Fei, Liu Jianfeng, and Liu Hong (picture source: screenshot of the official website of Nature).
In the second paper, the researchers pointed out the metabotropic glutamate receptor It can exist in the form of homology and heterodimer, and the pharmacological properties and functions of the two may be different
.

In the paper, the team also used cryo-electron microscopy technology to obtain four structures of mGlu2 and mGlu7, including inactive mGlu2 and mGlu7 homodimers, mGlu2 homodimers combined with agonists and positive allosteric modulators Polymers, and non-activated mGlu2-mGlu7 heterodimers
.

The analysis of these structures found some dimer patterns that depend on the subtypes of metabotropic glutamate receptors, providing more details of the molecular mechanism for the conformational changes within and between subunits
.

▲Schematic diagram of metabotropic glutamate receptor structure
.

The three mGlu2 structures in different functional states in the figure are represented by green ribbon diagrams, from the top left to the bottom right are inactive state, activated intermediate state and fully activated state
.

The three subunits of the G protein in the fully activated structure are represented by orange, gray, and blue (picture source: Wu Beili's research group) "Our research mainly focused on mGlu2, 4, and 7, among which mGlu2 was shot a lot.
'HD photos' in different states, from inactive, active intermediate state, to fully activated state
.

"Researcher Wu Beili said in an interview with "Wen Wei Po"
.

Taken together, from these "high-definition photos" of cryo-electron microscopy, the researchers found that metabotropic glutamate receptors belong to class C G protein coupled receptors and A class a, class B there is a clear difference
.

by these two studies, the first time we have a fine receptor conformational change under different activation states have a thorough knowledge of the metabotropic glutamate
.

considering the metabotropic glutamate receptor itself The important physiological role of and its potential role in many neurodevelopmental and psychiatric diseases, these findings will allow us to better understand this key molecule and serve future drug design
.

References: [1] Lin, S .
, Han, S.
, Cai, X.
et al.
Structures of Gi-bound metabotropic glutamate receptors mGlu2 and mGlu4.
Nature (2021).
https://doi.
org/10.
1038/s41586-021-03495-2[2 ] Du, J.
, Wang, D.
, Fan, H.
et al.
Structures of human mGlu2 and mGlu7 homo- and heterodimers.
Nature (2021).
https://doi.
org/10.
1038/s41586-021-03641- w[3] Two articles in the same period "Nature": Another potential target of Alzheimer's disease is seen, Retrieved June 16, 2021, from http://wenhui.
whb.
cn/zhuzhan/kjwz/20210616/409560 .
html