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. jmm@sund.ku.dk.
10 Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. yiorgo@stanford.edu.
11 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. yiorgo@stanford.edu.
12 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. kobilka@stanford.edu.
13 ConfometRx, Santa Clara, CA, USA. kobilka@stanford.edu.
# 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.

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