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Structural Insights into Metabotropic Glutamate Receptor Activation

Metabotropic glutamate receptors are Family C G protein coupled receptors that form obligate dimers and possess extracellular ligand binding Venus flytrap (VFT) domains, which are linked via cysteine rich domains (CRDs) to their 7-transmembrane (7TM) domain. Spectroscopic studies show that signaling...

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Autores principales: Koehl, Antoine, Hu, Hongli, Feng, Dan, Sun, Bingfa, Zhang, Yan, Robertson, Michael J, Chu, Matthew, Kobilka, Tong Sun, Pardon, Els, Steyaert, Jan, Tarrasch, Jeffrey, Dutta, Somnath, Fonseca, Rasmus, Weis, William I, Mathiesen, Jesper M, Skiniotis, Georgios, Kobilka, Brian K
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709600/
https://www.ncbi.nlm.nih.gov/pubmed/30675062
http://dx.doi.org/10.1038/s41586-019-0881-4
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author Koehl, Antoine
Hu, Hongli
Feng, Dan
Sun, Bingfa
Zhang, Yan
Robertson, Michael J
Chu, Matthew
Kobilka, Tong Sun
Pardon, Els
Steyaert, Jan
Tarrasch, Jeffrey
Dutta, Somnath
Fonseca, Rasmus
Weis, William I
Mathiesen, Jesper M
Skiniotis, Georgios
Kobilka, Brian K
author_facet Koehl, Antoine
Hu, Hongli
Feng, Dan
Sun, Bingfa
Zhang, Yan
Robertson, Michael J
Chu, Matthew
Kobilka, Tong Sun
Pardon, Els
Steyaert, Jan
Tarrasch, Jeffrey
Dutta, Somnath
Fonseca, Rasmus
Weis, William I
Mathiesen, Jesper M
Skiniotis, Georgios
Kobilka, Brian K
author_sort Koehl, Antoine
collection PubMed
description Metabotropic glutamate receptors are Family C G protein coupled receptors that form obligate dimers and possess extracellular ligand binding Venus flytrap (VFT) domains, which are linked via cysteine rich domains (CRDs) to their 7-transmembrane (7TM) domain. Spectroscopic studies show that signaling is a dynamic process, with large scale conformational changes underlying the transmission of signal from the extracellular VFTs to the G protein-coupling domains (7TMs) in the membrane. Using a combination of x-ray crystallography, cryo-electron microscopy and signaling studies, we present a structural framework for the activation mechanism of metabotropic glutamate receptor subtype 5. Our results show that agonist binding at the VFTs leads to a compaction of the intersubunit dimer interface, thereby bringing the CRDs into close proximity. Interactions between the CRDs and the second extracellular loops of the receptor enable the rigid body repositioning of the 7TM domains, which come into contact with each other to initiate signaling.
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spelling pubmed-67096002019-08-26 Structural Insights into Metabotropic Glutamate Receptor Activation Koehl, Antoine Hu, Hongli Feng, Dan Sun, Bingfa Zhang, Yan Robertson, Michael J Chu, Matthew Kobilka, Tong Sun Pardon, Els Steyaert, Jan Tarrasch, Jeffrey Dutta, Somnath Fonseca, Rasmus Weis, William I Mathiesen, Jesper M Skiniotis, Georgios Kobilka, Brian K Nature Article Metabotropic glutamate receptors are Family C G protein coupled receptors that form obligate dimers and possess extracellular ligand binding Venus flytrap (VFT) domains, which are linked via cysteine rich domains (CRDs) to their 7-transmembrane (7TM) domain. Spectroscopic studies show that signaling is a dynamic process, with large scale conformational changes underlying the transmission of signal from the extracellular VFTs to the G protein-coupling domains (7TMs) in the membrane. Using a combination of x-ray crystallography, cryo-electron microscopy and signaling studies, we present a structural framework for the activation mechanism of metabotropic glutamate receptor subtype 5. Our results show that agonist binding at the VFTs leads to a compaction of the intersubunit dimer interface, thereby bringing the CRDs into close proximity. Interactions between the CRDs and the second extracellular loops of the receptor enable the rigid body repositioning of the 7TM domains, which come into contact with each other to initiate signaling. 2019-01-23 2019-02 /pmc/articles/PMC6709600/ /pubmed/30675062 http://dx.doi.org/10.1038/s41586-019-0881-4 Text en Reprints and permissions information is available at www.nature.com/reprints (http://www.nature.com/reprints) . Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Koehl, Antoine
Hu, Hongli
Feng, Dan
Sun, Bingfa
Zhang, Yan
Robertson, Michael J
Chu, Matthew
Kobilka, Tong Sun
Pardon, Els
Steyaert, Jan
Tarrasch, Jeffrey
Dutta, Somnath
Fonseca, Rasmus
Weis, William I
Mathiesen, Jesper M
Skiniotis, Georgios
Kobilka, Brian K
Structural Insights into Metabotropic Glutamate Receptor Activation
title Structural Insights into Metabotropic Glutamate Receptor Activation
title_full Structural Insights into Metabotropic Glutamate Receptor Activation
title_fullStr Structural Insights into Metabotropic Glutamate Receptor Activation
title_full_unstemmed Structural Insights into Metabotropic Glutamate Receptor Activation
title_short Structural Insights into Metabotropic Glutamate Receptor Activation
title_sort structural insights into metabotropic glutamate receptor activation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709600/
https://www.ncbi.nlm.nih.gov/pubmed/30675062
http://dx.doi.org/10.1038/s41586-019-0881-4
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