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Nature. 2019 Feb;566(7742):79-84. doi: 10.1038/s41586-019-0881-4. Epub 2019 Jan 23.

Structural insights into the activation of metabotropic glutamate receptors.

Author information

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.

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.

PMID:
30675062
DOI:
10.1038/s41586-019-0881-4
[Indexed for MEDLINE]

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