skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Structure and functional interaction of the extracellular domain of human GABA[subscript B] receptor GBR2

Abstract

Inhibitory neurotransmission is mediated primarily by GABA. The metabotropic GABA{sub B} receptor is a G protein-coupled receptor central to mammalian brain function. Malfunction of GABA{sub B} receptor has been implicated in several neurological disorders. GABA{sub B} receptor functions as a heterodimeric assembly of GBR1 and GBR2 subunits, where GBR1 is responsible for ligand-binding and GBR2 is responsible for G protein coupling. Here we demonstrate that the GBR2 ectodomain directly interacts with the GBR1 ectodomain to increase agonist affinity by selectively stabilizing the agonist-bound conformation of GBR1. We present the crystal structure of the GBR2 ectodomain, which reveals a polar heterodimeric interface. We also identify specific heterodimer contacts from both subunits, and GBR1 residues involved in ligand recognition. Lastly, our structural and functional data indicate that the GBR2 ectodomain adopts a constitutively open conformation, suggesting a structural asymmetry in the active state of GABA{sub B} receptor that is unique to the GABAergic system.

Authors:
; ; ; ; ; ; ; ; ; ; ;  [1];  [2]
  1. (CNRS-UMR)
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1046856
Resource Type:
Journal Article
Journal Name:
Nat. Neurosci.
Additional Journal Information:
Journal Volume: 15; Journal Issue: 2012
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; AFFINITY; ASYMMETRY; BRAIN; CRYSTAL STRUCTURE; FUNCTIONALS; PROTEINS; RESIDUES

Citation Formats

Geng, Yong, Xiong, Dazhi, Mosyak, Lidia, Malito, David L., Kniazeff, Julie, Chen, Yan, Burmakina, Svetlana, Quick, Matthias, Bush, Martin, Javitch, Jonathan A., Pin, Jean-Philippe, Fan, Qing R., and Columbia). Structure and functional interaction of the extracellular domain of human GABA[subscript B] receptor GBR2. United States: N. p., 2012. Web. doi:10.1038/nn.3133.
Geng, Yong, Xiong, Dazhi, Mosyak, Lidia, Malito, David L., Kniazeff, Julie, Chen, Yan, Burmakina, Svetlana, Quick, Matthias, Bush, Martin, Javitch, Jonathan A., Pin, Jean-Philippe, Fan, Qing R., & Columbia). Structure and functional interaction of the extracellular domain of human GABA[subscript B] receptor GBR2. United States. doi:10.1038/nn.3133.
Geng, Yong, Xiong, Dazhi, Mosyak, Lidia, Malito, David L., Kniazeff, Julie, Chen, Yan, Burmakina, Svetlana, Quick, Matthias, Bush, Martin, Javitch, Jonathan A., Pin, Jean-Philippe, Fan, Qing R., and Columbia). Wed . "Structure and functional interaction of the extracellular domain of human GABA[subscript B] receptor GBR2". United States. doi:10.1038/nn.3133.
@article{osti_1046856,
title = {Structure and functional interaction of the extracellular domain of human GABA[subscript B] receptor GBR2},
author = {Geng, Yong and Xiong, Dazhi and Mosyak, Lidia and Malito, David L. and Kniazeff, Julie and Chen, Yan and Burmakina, Svetlana and Quick, Matthias and Bush, Martin and Javitch, Jonathan A. and Pin, Jean-Philippe and Fan, Qing R. and Columbia)},
abstractNote = {Inhibitory neurotransmission is mediated primarily by GABA. The metabotropic GABA{sub B} receptor is a G protein-coupled receptor central to mammalian brain function. Malfunction of GABA{sub B} receptor has been implicated in several neurological disorders. GABA{sub B} receptor functions as a heterodimeric assembly of GBR1 and GBR2 subunits, where GBR1 is responsible for ligand-binding and GBR2 is responsible for G protein coupling. Here we demonstrate that the GBR2 ectodomain directly interacts with the GBR1 ectodomain to increase agonist affinity by selectively stabilizing the agonist-bound conformation of GBR1. We present the crystal structure of the GBR2 ectodomain, which reveals a polar heterodimeric interface. We also identify specific heterodimer contacts from both subunits, and GBR1 residues involved in ligand recognition. Lastly, our structural and functional data indicate that the GBR2 ectodomain adopts a constitutively open conformation, suggesting a structural asymmetry in the active state of GABA{sub B} receptor that is unique to the GABAergic system.},
doi = {10.1038/nn.3133},
journal = {Nat. Neurosci.},
number = 2012,
volume = 15,
place = {United States},
year = {2012},
month = {10}
}