Promiscuity and selectivity of bitter molecules and their receptors.
Bitter taste is essential for survival, as it protects against consuming poisonous compounds, which are often bitter. Bitter taste perception is mediated by bitter taste receptors (TAS2Rs), a subfamily of G-protein coupled receptors (GPCRs). The number of TAS2R subtypes is species-dependent, and varies from 3 in chicken to 50 in frog. TAS2Rs present an intriguing case for studying promiscuity: some of the receptors are still orphan, or have few known agonists, while others can be activated by numerous, structurally dissimilar compounds. The ligands also vary in the repertoire of TAS2Rs that they activate: some bitter compounds are selective toward a single TAS2R, while others activate multiple TAS2Rs. Selectivity/promiscuity profile of bitter taste receptors and their compounds was explored by a chemoinformatic approach. TAS2R-promiscuous and TAS2R-selective bitter molecules were found to differ in chemical features, such as AlogP, E-state, total charge, number of rings, globularity, and heavy atom count. This allowed the prediction of bitter ligand selectivity toward TAS2Rs. Interestingly, while promiscuous TAS2Rs are activated by both TAS2R-promiscuous and TAS2R-selective compounds, almost all selective TAS2Rs in human are activated by promiscuous compounds, which are recognized by other TAS2Rs anyway. Thus, unique ligands, that may have been the evolutionary driving force for development of selective TAS2Rs, still need to be unraveled.
Institute of Biochemistry, Food Science and Nutrition, Robert H Smith Faculty of Agriculture Food and Environment, The Hebrew University, Rehovot 76100, Israel; Fritz Haber Center for Molecular Dynamics, The Hebrew University, Jerusalem 91904, Israel.
Antonella
A
Di Pizio
Institute of Biochemistry, Food Science and Nutrition, Robert H Smith Faculty of Agriculture Food and Environment, The Hebrew University, Rehovot 76100, Israel; Fritz Haber Center for Molecular Dynamics, The Hebrew University, Jerusalem 91904, Israel. Electronic address: masha.niv@mail.huji.ac.il.
Masha Y
MY
Niv
D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D008024:Ligands; D008962:Models, Theoretical; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013649:Taste
D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D054852:Small Molecule Libraries; C568609:TAS2R1 protein, human
Canonical binding site; Chemical senses; Chemosensory; GPCR; Modeling; Molecular recognition; Orthosteric