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Nat Chem Biol. 2015 Feb;11(2):134-40. doi: 10.1038/nchembio.1711. Epub 2014 Dec 15.

Major ligand-induced rearrangement of the heptahelical domain interface in a GPCR dimer.

Author information

1
1] Cellular Signaling Laboratory, Key Laboratory of Molecular Biophysics of Ministry of Education, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. [2] CNRS, UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France. [3] INSERM, U661, Montpellier, France. [4] Université Montpellier 1 &2, Montpellier, France.
2
1] CNRS, UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France. [2] INSERM, U661, Montpellier, France. [3] Université Montpellier 1 &2, Montpellier, France.
3
Cellular Signaling Laboratory, Key Laboratory of Molecular Biophysics of Ministry of Education, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.

Abstract

G protein-coupled receptors (GPCRs) are major players in cell communication. Although they form functional monomers, increasing evidence indicates that GPCR dimerization has a critical role in cooperative phenomena that are important for cell signal integration. However, the structural bases of these phenomena remain elusive. Here, using well-characterized receptor dimers, the metabotropic glutamate receptors (mGluRs), we show that structural changes at the dimer interface are linked to receptor activation. We demonstrate that the main dimer interface is formed by transmembrane α helix 4 (TM4) and TM5 in the inactive state and by TM6 in the active state. This major change in the dimer interface is required for receptor activity because locking the TM4-TM5 interface prevents activation by agonist, whereas locking the TM6 interface leads to a constitutively active receptor. These data provide important information on the activation mechanism of mGluRs and improve our understanding of the structural basis of the negative cooperativity observed in these GPCR dimers.

PMID:
25503927
DOI:
10.1038/nchembio.1711
[Indexed for MEDLINE]

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