Structural insights into the activation of metabotropic glutamate receptors

Antoine Koehl, Hongli Hu, Dan Feng, Bingfa Sun, Yan Zhang, Michael J. Robertson, Matthew Chu, Tong Sun Kobilka, Toon Laeremans, Jan Steyaert, Jeffrey Tarrasch, Somnath Dutta, Rasmus Fonseca, William I. Weis, Jesper M. Mathiesen (), Georgios Skiniotis () and Brian K. Kobilka ()
Additional contact information
Antoine Koehl: Stanford University School of Medicine
Hongli Hu: Stanford University School of Medicine
Dan Feng: ConfometRx
Bingfa Sun: ConfometRx
Yan Zhang: Stanford University School of Medicine
Michael J. Robertson: Stanford University School of Medicine
Matthew Chu: ConfometRx
Tong Sun Kobilka: Stanford University School of Medicine
Toon Laeremans: Vrije Universiteit Brussel (VUB)
Jan Steyaert: Vrije Universiteit Brussel (VUB)
Jeffrey Tarrasch: University of Michigan Medical School
Somnath Dutta: University of Michigan Medical School
Rasmus Fonseca: Stanford University School of Medicine
William I. Weis: Stanford University School of Medicine
Jesper M. Mathiesen: University of Copenhagen
Georgios Skiniotis: Stanford University School of Medicine
Brian K. Kobilka: Stanford University School of Medicine

Nature, 2019, vol. 566, issue 7742, 79-84

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-0881-4

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