Structural Insights into Metabotropic Glutamate Receptor Activation

Autor: 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
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Nature
ISSN: 1476-4687
0028-0836
Popis: 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.
Databáze: OpenAIRE
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