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Evidence for a Transient Additional Ligand Binding Site in the TAS2R46 Bitter Taste Receptor

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Computational Biophysics, German Research School for Simulation Sciences, 52425 Jülich, Germany
Department of Molecular Genetics, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany
§ 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
Department of Biotechnology, University of Verona, Ca’ Vignal 1, Strada Le Grazie 15, 37134 Verona, Italy
# ○ #Computational Biomedicine, Institute for Advanced Simulation IAS-5, and Computational Biomedicine, Institute of Neuroscience and Medicine INM-9,Forschungszentrum Jülich, 52425 Jülich, Germany
*E-mail: [email protected] (A.G.).
*E-mail: [email protected] (P.C.).
Cite this: J. Chem. Theory Comput. 2015, 11, 9, 4439–4449
Publication Date (Web):August 12, 2015
https://doi.org/10.1021/acs.jctc.5b00472
Copyright © 2015 American Chemical Society

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    Abstract

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    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.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jctc.5b00472.

    • Supporting Information 1–18 show alignments and parameters used for the modeling and docking procedures, model numbering and topology, details of system evolution during simulation including hydration, details of the second vestibular pose, residue–ligand contact map, discussion of experimental limitations, location and effect of experimentally mutated residues, details of intramolecular interactions, details of the A268R simulation, and effects of attempts to force experimentally identified residues into a single binding pose (PDF)

    • Coordinates of the TAS2R46 homology model

      (PDB)

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