Volume 33, No 9, Sep 2023

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 33 Issue 9, September 2023: 699-711   |  Open Access

ORIGINAL ARTICLES

Structural insights into dimerization and activation of the mGlu2–mGlu3 and mGlu2–mGlu4 heterodimers

Xinwei Wang^1,2,† , Mu Wang^1,3,† , Tuo Xu^1,2,† , Ye Feng^1,3,† , Qiang Shao^1,2,† , Shuo Han^1,2,4 , Xiaojing Chu¹ , Yechun Xu^1,2,4 , Shuling Lin^1,* , Qiang Zhao^1,2,5,* , Beili Wu^1,2,3,4,*

¹State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
²University of Chinese Academy of Sciences, Beijing, China
³School of Life Science and Technology, ShanghaiTech University, Shanghai, China
⁴School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China
⁵Zhongshan Institute of Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, Guangdong, China
^†These authors contributed equally: Xinwei Wang, Mu Wang, Tuo Xu, Ye Feng, Qiang Shao
Correspondence: Shuling Lin(linshuling@simm.ac.cn)Qiang Zhao(zhaoq@simm.ac.cn)Beili Wu(beiliwu@simm.ac.cn)

Heterodimerization of the metabotropic glutamate receptors (mGlus) has shown importance in the functional modulation of the receptors and offers potential drug targets for treating central nervous system diseases. However, due to a lack of molecular details of the mGlu heterodimers, understanding of the mechanisms underlying mGlu heterodimerization and activation is limited. Here we report twelve cryo-electron microscopy (cryo-EM) structures of the mGlu2–mGlu3 and mGlu2–mGlu4 heterodimers in different conformational states, including inactive, intermediate inactive, intermediate active and fully active conformations. These structures provide a full picture of conformational rearrangement of mGlu2–mGlu3 upon activation. The Venus flytrap domains undergo a sequential conformational change, while the transmembrane domains exhibit a substantial rearrangement from an inactive, symmetric dimer with diverse dimerization patterns to an active, asymmetric dimer in a conserved dimerization mode. Combined with functional data, these structures reveal that stability of the inactive conformations of the subunits and the subunit–G protein interaction pattern are determinants of asymmetric signal transduction of the heterodimers. Furthermore, a novel binding site for two mGlu4 positive allosteric modulators was observed in the asymmetric dimer interfaces of the mGlu2–mGlu4 heterodimer and mGlu4 homodimer, and may serve as a drug recognition site. These findings greatly extend our knowledge about signal transduction of the mGlus.

https://doi.org/10.1038/s41422-023-00830-2

FULL TEXT | PDF

Browse 596