Structural insights into the activation of metabotropic glutamate receptors

Koehl, Antoine and Hu, Hongli and Feng, Dan and Sun, Bingfa and Zhang, Yan and Robertson, Michael J and Chu, Matthew and Kobilka, Tong Sun and Laermans, Toon and Steyaert, Jan and Tarrasch, Jeffrey and Dutta, Somnath and Fonseca, Rasmus and Weis, William I and Mathiesen, Jesper M and Skiniotis, Georgios and Kobilka, Brian K (2019) Structural insights into the activation of metabotropic glutamate receptors. In: NATURE, 566 (7742). 79+.

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Abstract

Metabotropic glutamate receptors are family C G-protein-coupled receptors. They form obligate dimers and possess extracellular ligand-binding Venus flytrap domains, which are linked by cysteine-rich domains to their 7-transmembrane domains. Spectroscopic studies show that signalling is a dynamic process, in which large-scale conformational changes underlie the transmission of signals from the extracellular Venus flytraps to the G protein-coupling domains-the 7-transmembrane domains-in the membrane. Here, using a combination of X-ray crystallography, cryo-electron microscopy and signalling studies, we present a structural framework for the activation mechanism of metabotropic glutamate receptor subtype 5. Our results show that agonist binding at the Venus flytraps leads to a compaction of the intersubunit dimer interface, thereby bringing the cysteine-rich domains into close proximity. Interactions between the cysteine-rich domains and the second extracellular loops of the receptor enable the rigid-body repositioning of the 7-transmembrane domains, which come into contact with each other to initiate signalling.

Item Type:	Journal Article
Publication:	NATURE
Publisher:	NATURE PUBLISHING GROUP
Additional Information:	Copyright of this article belongs to NATURE PUBLISHING GROUP
Department/Centre:	Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited:	25 Feb 2019 04:53
Last Modified:	25 Feb 2019 04:53
URI:	http://eprints.iisc.ac.in/id/eprint/61815

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