Exploring the activation mechanism of metabotropic glutamate receptor 2

Author:

Zhu Xiaohong12,Luo Mengqi3,An Ke4,Shi Danfeng12,Hou Tingjun5,Warshel Arieh6,Bai Chen14

Affiliation:

1. Warshel Institute for Computational Biology, School of Life and Health Sciences, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong 518172, People’s Republic of China

2. School of Chemistry and Materials Science, University of Science and Technology of China, Hefei 230026, People's Republic of China

3. College of Management, Shenzhen University, Shenzhen 518060, People's Republic of China

4. Chenzhu (MoMeD) Biotechnology Co., Ltd, Hangzhou, Zhejiang 310005, People's Republic of China

5. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China

6. Department of Chemistry, University of Southern California, Los Angeles, CA 90089-1062

Abstract

Homomeric dimerization of metabotropic glutamate receptors (mGlus) is essential for the modulation of their functions and represents a promising avenue for the development of novel therapeutic approaches to address central nervous system diseases. Yet, the scarcity of detailed molecular and energetic data on mGlu2 impedes our in-depth comprehension of their activation process. Here, we employ computational simulation methods to elucidate the activation process and key events associated with the mGlu2, including a detailed analysis of its conformational transitions, the binding of agonists, G i protein coupling, and the guanosine diphosphate (GDP) release. Our results demonstrate that the activation of mGlu2 is a stepwise process and several energy barriers need to be overcome. Moreover, we also identify the rate-determining step of the mGlu2’s transition from the agonist-bound state to its active state. From the perspective of free-energy analysis, we find that the conformational dynamics of mGlu2’s subunit follow coupled rather than discrete, independent actions. Asymmetric dimerization is critical for receptor activation. Our calculation results are consistent with the observation of cross-linking and fluorescent-labeled blot experiments, thus illustrating the reliability of our calculations. Besides, we also identify potential key residues in the G i protein binding position on mGlu2, mGlu2 dimer’s TM6–TM6 interface, and Gi α5 helix by the change of energy barriers after mutation. The implications of our findings could lead to a more comprehensive grasp of class C G protein-coupled receptor activation.

Funder

the National Natural Science Foundation of Youth Fund Project

the National Natural Science Foundation of China

the 2021 Basic Research General Project of Shenzhen, China

the National Institutes of Health

the National Science Foundation Grant

Publisher

Proceedings of the National Academy of Sciences

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