Structural insights into the activation of metabotropic glutamate receptors

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.

doi:10.1038/s41586-019-0881-4

Title: Structural insights into the activation of metabotropic glutamate receptors

Journal Article · Wed Jan 23 00:00:00 EST 2019 · Nature (London)

DOI:https://doi.org/10.1038/s41586-019-0881-4· OSTI ID:1503075

Koehl, Antoine ^[1]; Hu, Hongli ^[1]; Feng, Dan ^[2]; Sun, Bingfa ^[2]; Zhang, Yan ^[1]; Robertson, Michael J. ^[1]; Chu, Matthew ^[2]; Kobilka, Tong Sun ^[3]; Laeremans, Toon ^[4]; Steyaert, Jan ^[4]; Tarrasch, Jeffrey ^[5]; Dutta, Somnath ^[6]; Fonseca, Rasmus ^[7]; Weis, William I. ^[1]; Mathiesen, Jesper M. ^[8]; Skiniotis, Georgios ^[1]; Kobilka, Brian K. ^[1]

Stanford Univ. School of Medicine, Stanford, CA (United States)
ConfometRx, Santa Clara, CA (United States)
Stanford Univ. School of Medicine, Stanford, CA (United States); ConfometRx, Santa Clara, CA (United States)
Vrije Univ. Brussel (VUB), Brussels (Belgium); VIB-VUB Center for Structural Biology, Brussels (Belgium)
Univ. of Michigan, Ann Arbor, MI (United States)
Univ. of Michigan, Ann Arbor, MI (United States); Indian Institute of Science, Bangalore (India)
Stanford Univ. School of Medicine, Stanford, CA (United States); Stanford Univ., Stanford, CA (United States)
Univ. of Copenhagen, Copenhagen (Denmark)

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.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1503075

Journal Information:: Nature (London), Vol. 566, Issue 7742; ISSN 0028-0836

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 167 works

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