title: Evidence for a Transient Additional Ligand Binding Site in the TAS2R46 Bitter Taste Receptor.
abstract: Most human G protein coupled receptors (GPCRs) are activated by small molecules binding to their 7-transmembrane (7-TM) helix bundle. They belong to basally diverging branches: the 25 bitter taste 2 receptors and most members of the very large rhodopsin-like/class A GPCRs subfamily. Some members of the class A branch have been suggested to feature not only an orthosteric agonist-binding site but also a more extracellular or "vestibular" site, involved in the binding process. Here we use a hybrid molecular mechanics/coarse-grained (MM/CG) molecular dynamics approach on a widely studied bitter taste receptor (TAS2R46) receptor in complex with its agonist strychnine. Three ∼1 μs molecular simulation trajectories find two sites hosting the agonist, which together elucidate experimental data measured previously and in this work. This mechanism shares similarities with the one suggested for the evolutionarily distant class A GPCRs. It might be instrumental for the remarkably broad but specific spectrum of agonists of these chemosensory receptors.
authors.affiliation: Computational Biophysics, German Research School for Simulation Sciences , 52425 Jülich, Germany.
authors.forename: Massimo
authors.initials: M
authors.lastname: Sandal
authors.affiliation: Department of Molecular Genetics, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE) , Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany.
authors.forename: Maik
authors.initials: M
authors.lastname: Behrens
authors.affiliation: Department of Molecular Genetics, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE) , Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Brockhoff
authors.affiliation: Scuola Internazionale Superiore di Studi Avanzati (SISSA/ISAS) , Via Bonomea 265, 34151 Trieste, Italy.|Laboratory of Bioinorganic Chemistry, Department of Pharmacy and Biotechnology (FaBIT), University of Bologna , Viale Giuseppe Fanin 40, I-40127, Bologna, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Musiani
authors.affiliation: Computational Biophysics, German Research School for Simulation Sciences , 52425 Jülich, Germany.|Department of Biotechnology, University of Verona , Ca' Vignal 1, Strada Le Grazie 15, 37134 Verona, Italy.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Giorgetti
authors.affiliation: Computational Biophysics, German Research School for Simulation Sciences , 52425 Jülich, Germany.
authors.forename: Paolo
authors.initials: P
authors.lastname: Carloni
authors.affiliation: Department of Molecular Genetics, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE) , Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Meyerhof
mesh_terms: D001665:Binding Sites; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013331:Strychnine / Q000737:chemistry* / Q000494:pharmacology; D000098706:Taste Receptors, Type 2
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D000098706:Taste Receptors, Type 2; D013331:Strychnine