• 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
Pages (from-to)79–84
Number of pages6
Issue number7742
Early online date23 Jan 2019
Publication statusPublished - 7 Feb 2019

ID: 43921804