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 for this work

Department of Computer Science

95 Citations (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.

Original language	English
Journal	Nature
Volume	566
Issue number	7742
Pages (from-to)	79-84
Number of pages	6
ISSN	0028-0836
DOIs	https://doi.org/10.1038/s41586-019-0881-4
Publication status	Published - 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.",

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AU - Hu, Hongli

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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

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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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