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 Laermans; Jan Steyaert; Jeffrey Tarrasch; Somnath Dutta; Rasmus Fonseca; William I. Weis; Jesper M. Mathiesen; Georgios Skiniotis; Brian K. Kobilka

doi:10.1038/s41586-019-0881-4

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 Laermans, Jan Steyaert, Jeffrey Tarrasch, Somnath Dutta, Rasmus Fonseca, William I. Weis, Jesper M. Mathiesen, Georgios Skiniotis^*, Brian K. Kobilka

^*Corresponding author af dette arbejde

Datalogisk Institut

95 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Nature
Vol/bind	566
Udgave nummer	7742
Sider (fra-til)	79-84
Antal sider	6
ISSN	0028-0836
DOI	https://doi.org/10.1038/s41586-019-0881-4
Status	Udgivet - 7 feb. 2019

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Koehl, A., Hu, H., Feng, D., Sun, B., Zhang, Y., Robertson, M. J., Chu, M., Kobilka, T. S., Laermans, T., Steyaert, J., Tarrasch, J., Dutta, S., Fonseca, R., Weis, W. I., Mathiesen, J. M., Skiniotis, G., & Kobilka, B. K. (2019). Structural insights into the activation of metabotropic glutamate receptors. Nature, 566(7742), 79-84. https://doi.org/10.1038/s41586-019-0881-4

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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.",

author = "Antoine Koehl and Hongli Hu and Dan Feng and Bingfa Sun and Yan Zhang and Robertson, {Michael J.} and Matthew Chu and Kobilka, {Tong Sun} and Toon Laermans and Jan Steyaert and Jeffrey Tarrasch and Somnath Dutta and Rasmus Fonseca and Weis, {William I.} and Mathiesen, {Jesper M.} and Georgios Skiniotis and Kobilka, {Brian K.}",

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AU - Hu, Hongli

AU - Feng, Dan

AU - Sun, Bingfa

AU - Zhang, Yan

AU - Robertson, Michael J.

AU - Chu, Matthew

AU - Kobilka, Tong Sun

AU - Laermans, Toon

AU - Steyaert, Jan

AU - Tarrasch, Jeffrey

AU - Dutta, Somnath

AU - Fonseca, Rasmus

AU - Weis, William I.

AU - Mathiesen, Jesper M.

AU - Skiniotis, Georgios

AU - Kobilka, Brian K.

PY - 2019/2/7

Y1 - 2019/2/7

N2 - 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.

AB - 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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Structural insights into the activation of metabotropic glutamate receptors

Abstract

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