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Title: Multi-scale simulations of membrane proteins: The case of bitter taste receptors
Authors: Suku, Eda
Fierro, Fabrizio
Giorgetti, Alejandro
Alfonso-Prieto, Mercedes
Carloni, Paolo
Keywords: G-protein coupled receptor;Bitter taste receptor;Molecular mechanics/coarse grained;Simulations;TAS2R38;TAS2R46
Issue Date: 2017
Publisher: H. : ĐHQGHN
Abstract: Human bitter taste receptors (hTAS2Rs) are the second largest group of chemosensory G-protein coupled receptors (25 members). hTAS2Rs are expressed in many tissues (e.g. tongue, gastrointestinal tract, respiratory system, brain, etc.), performing a variety of functions, from bitter taste perception to hormone secretion and bronchodilation. Due to the lack of experimental structural information, computations are currently the methods of choice to get insights into ligandereceptor interactions. Here we review our efforts at predicting the binding pose of agonists to hTAS2Rs, using state-of-the-art bioinformatics ap-proaches followed by hybrid Molecular Mechanics/Coarse-Grained (MM/CG) simulations. The latter method, developed by us, describes atomistically only the agonist binding region, including hydration, and it may be particularly suited to be used when bioinformatics predictions generate very low-resolution models, such as the case of hTAS2Rs. Our structural predictions of the hTAS2R38 and hTAS2R46 receptors in complex with their agonists turn out to be fully consistent with experimental mutagenesis data. In addition, they suggest a two-binding site architecture in hTAS2R46, consisting of the usual orthosteric site together with a“vestibular”site toward the extracellular space, as observed in other GPCRs. The presence of the vestibular site may help to discriminate among the wide spectrum of bitter ligands.
Description: p. 15-21
ISSN: 2468-2284
Appears in Collections:Advanced Materials and Devices

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