Molecular Biomechanics of the TAS2R46 Bitter Taste Receptor through Network-based Investigation

Abstract

AbstractThe intricate relationship between structural characteristics and the resultant signal-processing events is fundamental in comprehending the functions and mechanisms inherent in biomolecular systems, specifically proteins. G protein-coupled receptors (GPCRs) constitute one of the most prevalent protein families within the human organism, engaging in a wide spectrum of vital functions. The TAS2Rs, a subfamily of G protein-coupled receptors (GPCRs), play a primary role in recognizing bitter molecules and initiate a cascade of events leading to the perception of a bitter taste. This gustatory sensation is associated with protecting the organism against the ingestion of spoiled or poisonous food. Interestingly, TAS2Rs function is not limited to taste evaluation, but it is associated with many diseases as they are expressed in several extra-oral tissues. Since the precise mechanism of TAS2R activation is poorly understood, this work aims to characterize the mechanisms underlying the signal transduction on the recently experimentally solved hTAS2R46 bitter taste receptor using molecular dynamics simulations coupled with network-based analysis. The results show that receptor activation is associated with a more correlated dynamics of the receptor and the formation of an interaction between two helices which mainly convey the signal transferring from the extracellular to the intracellular region. By highlighting TAS2R46 activation hallmarks and proposing a methodology for the characterization of bitter taste receptor activation, this study lays the foundation for a general understanding of the functioning mechanisms of this fascinating class of receptors.HighlightsThe dynamics of active and inactive TAS2R46 were studied through network analysis.Ligand binding to TAS2R46 increases intra-protein correlations.TM3 and TM6 helices mediate the structural signalling in active TAS2R46.Rotation of Y241 residue is pivotal for the structural signalling in active TAS2R46.