Understanding the signalling pathway of the GnRH receptor: a molecular dynamics study

Abstract The signalling mechanism of G-protein coupled receptors has been broadly studied, however, due to their structural complexity, details of the signalling pathway remain unclear. Here we present molecular dynamics (MD) simulations that reveal the conformational changes of the GnRH receptor (GnRH1R) induced by interaction with the gonadotropin-releasing hormone (GnRH). A comparison between the GnRH1R conformation in the absence and presence of GnRH reveals specific conformational differences that characterise an active and inactive state of the receptor. Furthermore, we describe a detailed cascade of ligand-induced conformational changes in the GnRH receptor that can lead to intracellular signal transmission. We observe that following the initial interaction of GnRH, the signal travels via a particular activation switch triad (Glu90-Lys121-Ser124). This acts as the driving force for an intracellular loop to reposition and expose the G-protein orthosteric pocket. In contrast, in the absence of GnRH, the receptor adopts an inactive conformation, where the activation switch residues are separated while the G-protein binding site is sterically blocked. These findings will aid the discovery of new pharmaceuticals targeting GnRH1R, and they broaden understanding of the signal transmission process and hence the functionality of G-protein coupled receptors in general.