title: Probing the Binding Pocket of the Broadly Tuned Human Bitter Taste Receptor TAS2R14 by Chemical Modification of Cognate Agonists.
abstract: Sensing potentially harmful bitter substances in the oral cavity is achieved by a group of (˜) 25 receptors, named TAS2Rs, which are expressed in specialized sensory cells and recognize individual but overlapping sets of bitter compounds. The receptors differ in their tuning breadths ranging from narrowly to broadly tuned receptors. One of the most broadly tuned human bitter taste receptors is the TAS2R14 recognizing an enormous variety of chemically diverse synthetic and natural bitter compounds, including numerous medicinal drugs. This suggests that this receptor possesses a large readily accessible ligand binding pocket. To allow probing the accessibility and size of the ligand binding pocket, we chemically modified cognate agonists and tested receptor responses in functional assays. The addition of large functional groups to agonists was usually possible without abolishing agonistic activity. The newly synthesized agonist derivatives were modeled in the binding site of the receptor, providing comparison to the mother substances and rationalization of the in vitro activities of this series of compounds.
authors.affiliation: Bioorganic Chemistry Department, Faculty of Pharmacy, Al-Quds University, P.O. Box 20002, Jerusalem, Israel.
authors.forename: Rafik
authors.initials: R
authors.lastname: Karaman
authors.affiliation: Department of Molecular Genetics, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558, Nuthetal, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Nowak
authors.affiliation: The Institute of Biochemistry, Food and Nutrition, The Robert H Smith Faculty of Agriculture, Food and Environment, The Hebrew University, Rehovot, 76100, Israel.|The Fritz Haber Center for Molecular Dynamics, The Hebrew University, Jerusalem, 91904, Israel.
authors.forename: Antonella
authors.initials: A
authors.lastname: Di Pizio
authors.affiliation: Bioorganic Chemistry Department, Faculty of Pharmacy, Al-Quds University, P.O. Box 20002, Jerusalem, Israel.
authors.forename: Hothaifa
authors.initials: H
authors.lastname: Kitaneh
authors.affiliation: Bioorganic Chemistry Department, Faculty of Pharmacy, Al-Quds University, P.O. Box 20002, Jerusalem, Israel.
authors.forename: Alaa
authors.initials: A
authors.lastname: Abu-Jaish
authors.affiliation: Department of Molecular Genetics, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558, Nuthetal, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Meyerhof
authors.affiliation: The Institute of Biochemistry, Food and Nutrition, The Robert H Smith Faculty of Agriculture, Food and Environment, The Hebrew University, Rehovot, 76100, Israel.|The Fritz Haber Center for Molecular Dynamics, The Hebrew University, Jerusalem, 91904, Israel.
authors.forename: Masha Y
authors.initials: MY
authors.lastname: Niv
authors.affiliation: Department of Molecular Genetics, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558, Nuthetal, Germany.
authors.forename: Maik
authors.initials: M
authors.lastname: Behrens
mesh_terms: D001665:Binding Sites; D006801:Humans; D062105:Molecular Docking Simulation; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry*; D000098706:Taste Receptors, Type 2
chemical_list: D043562:Receptors, G-Protein-Coupled; D000098706:Taste Receptors, Type 2
keywords: TAS2R binding pocket; bitter taste receptor; chemical ligand design; functional calcium imaging; in silico homology modeling