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Conformational dynamics of a class C G-protein-coupled receptor.
- Source :
-
Nature [Nature] 2015 Aug 27; Vol. 524 (7566), pp. 497-501. Date of Electronic Publication: 2015 Aug 10. - Publication Year :
- 2015
-
Abstract
- G-protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors in eukaryotes. Crystal structures have provided insight into GPCR interactions with ligands and G proteins, but our understanding of the conformational dynamics of activation is incomplete. Metabotropic glutamate receptors (mGluRs) are dimeric class C GPCRs that modulate neuronal excitability, synaptic plasticity, and serve as drug targets for neurological disorders. A 'clamshell' ligand-binding domain (LBD), which contains the ligand-binding site, is coupled to the transmembrane domain via a cysteine-rich domain, and LBD closure seems to be the first step in activation. Crystal structures of isolated mGluR LBD dimers led to the suggestion that activation also involves a reorientation of the dimer interface from a 'relaxed' to an 'active' state, but the relationship between ligand binding, LBD closure and dimer interface rearrangement in activation remains unclear. Here we use single-molecule fluorescence resonance energy transfer to probe the activation mechanism of full-length mammalian group II mGluRs. We show that the LBDs interconvert between three conformations: resting, activated and a short-lived intermediate state. Orthosteric agonists induce transitions between these conformational states, with efficacy determined by occupancy of the active conformation. Unlike mGluR2, mGluR3 displays basal dynamics, which are Ca(2+)-dependent and lead to basal protein activation. Our results support a general mechanism for the activation of mGluRs in which agonist binding induces closure of the LBDs, followed by dimer interface reorientation. Our experimental strategy should be widely applicable to study conformational dynamics in GPCRs and other membrane proteins.
- Subjects :
- Animals
Binding Sites
Drug Partial Agonism
Humans
Ligands
Models, Biological
Models, Molecular
Protein Binding
Protein Conformation
Rats
Receptors, Metabotropic Glutamate genetics
Receptors, Metabotropic Glutamate metabolism
Fluorescence Resonance Energy Transfer
Receptors, Metabotropic Glutamate chemistry
Receptors, Metabotropic Glutamate classification
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 524
- Issue :
- 7566
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 26258295
- Full Text :
- https://doi.org/10.1038/nature14679