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Title: Structural insights into the activation of metabotropic glutamate receptors

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. Furthermore 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.
Authors:
 [1] ;  [1] ;  [2] ;  [2] ;  [1] ;  [1] ;  [2] ;  [3] ;  [4] ;  [4] ;  [5] ;  [6] ;  [7] ;  [1] ;  [8] ;  [1] ;  [1]
  1. Stanford Univ. School of Medicine, Stanford, CA (United States)
  2. ConfometRx, Santa Clara, CA (United States)
  3. Stanford Univ. School of Medicine, Stanford, CA (United States); ConfometRx, Santa Clara, CA (United States)
  4. Vrije Univ. Brussel (VUB), Brussels (Belgium); VIB-VUB Center for Structural Biology, Brussels (Belgium)
  5. Univ. of Michigan, Ann Arbor, MI (United States)
  6. Univ. of Michigan, Ann Arbor, MI (United States); Indian Institute of Science, Bangalore (India)
  7. Stanford Univ. School of Medicine, Stanford, CA (United States); Stanford Univ., Stanford, CA (United States)
  8. Univ. of Copenhagen, Copenhagen (Denmark)
Publication Date:
Grant/Contract Number:
AC02-76SF00515
Type:
Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Name: Nature (London); Journal Volume: 566; Journal Issue: 7742; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Research Org:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES
OSTI Identifier:
1503075

Koehl, Antoine, Hu, Hongli, Feng, Dan, Sun, Bingfa, Zhang, Yan, Robertson, Michael J., Chu, Matthew, Kobilka, Tong Sun, Laeremans, Toon, Steyaert, Jan, Tarrasch, Jeffrey, Dutta, Somnath, Fonseca, Rasmus, Weis, William I., Mathiesen, Jesper M., Skiniotis, Georgios, and Kobilka, Brian K.. Structural insights into the activation of metabotropic glutamate receptors. United States: N. p., Web. doi:10.1038/s41586-019-0881-4.
Koehl, Antoine, Hu, Hongli, Feng, Dan, Sun, Bingfa, Zhang, Yan, Robertson, Michael J., Chu, Matthew, Kobilka, Tong Sun, Laeremans, Toon, Steyaert, Jan, Tarrasch, Jeffrey, Dutta, Somnath, Fonseca, Rasmus, Weis, William I., Mathiesen, Jesper M., Skiniotis, Georgios, & Kobilka, Brian K.. Structural insights into the activation of metabotropic glutamate receptors. United States. doi:10.1038/s41586-019-0881-4.
Koehl, Antoine, Hu, Hongli, Feng, Dan, Sun, Bingfa, Zhang, Yan, Robertson, Michael J., Chu, Matthew, Kobilka, Tong Sun, Laeremans, Toon, Steyaert, Jan, Tarrasch, Jeffrey, Dutta, Somnath, Fonseca, Rasmus, Weis, William I., Mathiesen, Jesper M., Skiniotis, Georgios, and Kobilka, Brian K.. 2019. "Structural insights into the activation of metabotropic glutamate receptors". United States. doi:10.1038/s41586-019-0881-4.
@article{osti_1503075,
title = {Structural insights into the activation of metabotropic glutamate receptors},
author = {Koehl, Antoine and Hu, Hongli and Feng, Dan and Sun, Bingfa and Zhang, Yan and Robertson, Michael J. and Chu, Matthew and Kobilka, Tong Sun and Laeremans, Toon and Steyaert, Jan and Tarrasch, Jeffrey and Dutta, Somnath and Fonseca, Rasmus and Weis, William I. and Mathiesen, Jesper M. and Skiniotis, Georgios and Kobilka, Brian K.},
abstractNote = {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. Furthermore 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.},
doi = {10.1038/s41586-019-0881-4},
journal = {Nature (London)},
number = 7742,
volume = 566,
place = {United States},
year = {2019},
month = {1}
}

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RELION: Implementation of a Bayesian approach to cryo-EM structure determination
journal, December 2012