Ligand-guided homology modelling of the GABAb2 subunit of the GABAb receptor

Abstract

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 GABA_B receptor is a heterodimeric class C G protein-coupled receptor (GPCR) consisting of GABA_B1a/b and GABA_B2 subunits. Two GABA_B receptor ligand binding sites have been described, namely the orthosteric GABA binding site located in the extracellular GABA_B1 Venus fly trap domain and the allosteric binding site found in the GABA_B2 transmembrane domain. To date, the only experimentally solved three-dimensional structures of the GABA_B receptor are of the Venus fly trap domain. GABA_Breceptor allosteric modulators, however, show great therapeutic potential, and elucidating the structure of the GABA_B2 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 GABA_B2 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 GABA_B receptor. Here, multiple homology models of the GABA_B2 subunit of the GABA_B 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 GABA_B2 homology models have been chosen as possible structural representatives of the transmembrane domain of the GABA_B2 subunit. To the best of our knowledge, the present study is the first to describe homology modelling of the transmembrane domain of the GABA_B2 subunit and the docking of positive allosteric modulators in the receptor.