Ligand-guided homology modelling of the GABAB2 subunit of the GABAB receptor

PLoS One. 2017 Mar 21;12(3):e0173889. doi: 10.1371/journal.pone.0173889. eCollection 2017.


γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system, and disturbances in the GABAergic system have been implicated in numerous neurological and neuropsychiatric diseases. The GABAB receptor is a heterodimeric class C G protein-coupled receptor (GPCR) consisting of GABAB1a/b and GABAB2 subunits. Two GABAB receptor ligand binding sites have been described, namely the orthosteric GABA binding site located in the extracellular GABAB1 Venus fly trap domain and the allosteric binding site found in the GABAB2 transmembrane domain. To date, the only experimentally solved three-dimensional structures of the GABAB receptor are of the Venus fly trap domain. GABAB receptor allosteric modulators, however, show great therapeutic potential, and elucidating the structure of the GABAB2 transmembrane domain may lead to development of novel drugs and increased understanding of the allosteric mechanism of action. Despite the lack of x-ray crystal structures of the GABAB2 transmembrane domain, multiple crystal structures belonging to other classes of GPCRs than class A have been released within the last years. More closely related template structures are now available for homology modelling of the GABAB receptor. Here, multiple homology models of the GABAB2 subunit of the GABAB receptor have been constructed using templates from class A, B and C GPCRs, and docking of five clusters of positive allosteric modulators and decoys has been undertaken to select models that enrich the active compounds. Using this ligand-guided approach, eight GABAB2 homology models have been chosen as possible structural representatives of the transmembrane domain of the GABAB2 subunit. To the best of our knowledge, the present study is the first to describe homology modelling of the transmembrane domain of the GABAB2 subunit and the docking of positive allosteric modulators in the receptor.

MeSH terms

  • Allosteric Site
  • Humans
  • Ligands
  • Models, Molecular
  • Protein Domains
  • Protein Subunits
  • Receptors, GABA-B / chemistry*
  • Structural Homology, Protein


  • GABBR2 protein, human
  • Ligands
  • Protein Subunits
  • Receptors, GABA-B

Grant support

The study was partially supported by the Polish-Norwegian Research Program operated by the Polish National Centre for Research and Development under the Norwegian Financial Mechanism 2009-2014 in the frame of Project PLATFORMex (Pol-Nor/198887/73/2013). UiT The Arctic University of Norway contributed With PhD scholarship for TF and salary for MG and IS. The Polish Academy of Science funded DW, SM and AJB. The publication charges for this article have been funded by a grant from the publication fund of UiT The Arctic University of Norway.