Abstract
The metabotropic glutamate receptors (mGluRs) are key receptors in the modulation of excitatory synaptic transmission in the central nervous system. Here we have determined three different crystal structures of the extracellular ligand-binding region of mGluR1—in a complex with glutamate and in two unliganded forms. They all showed disulphide-linked homodimers, whose ‘active’ and ‘resting’ conformations are modulated through the dimeric interface by a packed α-helical structure. The bi-lobed protomer architectures flexibly change their domain arrangements to form an ‘open’ or ‘closed’ conformation. The structures imply that glutamate binding stabilizes both the ‘active’ dimer and the ‘closed’ protomer in dynamic equilibrium. Movements of the four domains in the dimer are likely to affect the separation of the transmembrane and intracellular regions, and thereby activate the receptor. This scheme in the initial receptor activation could be applied generally to G-protein-coupled neurotransmitter receptors that possess extracellular ligand-binding sites.
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Acknowledgements
We thank N. Yagi and Y. Katsuya for use of the facilities at SPring-8, Hyogo, Japan. We also thank T. Tomura and S. Yamamoto for technical assistance; H. Toh and T. Hiroike for their help in bioinformatic analyses; and Y. Shimura, H. Nakamura and A. Pähler for discussions and encouragement. This study is partly supported by a grant from the SPring-8 Joint Research Promotion Scheme of the Japan Science and Technology Corporation.
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Kunishima, N., Shimada, Y., Tsuji, Y. et al. Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature 407, 971–977 (2000). https://doi.org/10.1038/35039564
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DOI: https://doi.org/10.1038/35039564
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