Structural insights into the activation of metabotropic glutamate receptors

  • Nature. 2019 Feb;566(7742):79-84. doi: 10.1038/s41586-019-0881-4.
Antoine Koehl  #  1 ,  Hongli Hu  #  1  2 ,  Dan Feng  #  3 ,  Bingfa Sun  3 ,  Yan Zhang  1  2 ,  Michael J Robertson  1  2 ,  Matthew Chu  3 ,  Tong Sun Kobilka  2  3 ,  Toon Laeremans  4  5 ,  Jan Steyaert  4  5 ,  Jeffrey Tarrasch  6 ,  Somnath Dutta  6  7 ,  Rasmus Fonseca  1  2  8 ,  William I Weis  1  2 ,  Jesper M Mathiesen  9 ,  Georgios Skiniotis  10  11 ,  Brian K Kobilka  12  13
Affiliations
  • 1. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
  • 2. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
  • 3. ConfometRx, Santa Clara, CA, USA.
  • 4. Structural Biology Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
  • 5. VIB-VUB Center for Structural Biology, VIB, Brussels, Belgium.
  • 6. Life Sciences Institute and Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 7. Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India.
  • 8. Biosciences Division, SLAC National Accelerator Laboratory, Stanford University, Stanford, CA, USA.
  • 9. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. [email protected].
  • 10. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
  • 11. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
  • 12. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
  • 13. ConfometRx, Santa Clara, CA, USA. [email protected].
  • # Contributed equally.
PMID: 30675062 DOI: 10.1038/s41586-019-0881-4
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.