Structural insights into the activation of metabotropic glutamate receptors

Research output: Contribution to journalJournal articleResearchpeer-review

Antoine Koehl, Hongli Hu, Dan Feng, Bingfa Sun, Yan Zhang, Michael J. Robertson, Matthew Chu, Tong Sun Kobilka, Toon Laermans, Jan Steyaert, Jeffrey Tarrasch, Somnath Dutta, Rasmus Fonseca, William I. Weis, Jesper M. Mathiesen, Georgios Skiniotis, Brian K. Kobilka

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.

Original languageEnglish
JournalNature
Volume566
Issue number7742
Pages (from-to)79-84
Number of pages6
ISSN0028-0836
DOIs
Publication statusPublished - 7 Feb 2019

ID: 221756879