title: Coarse-grained/molecular mechanics of the TAS2R38 bitter taste receptor: experimentally-validated detailed structural prediction of agonist binding.
abstract: Bitter molecules in humans are detected by ∼25 G protein-coupled receptors (GPCRs). The lack of atomic resolution structure for any of them is complicating an in depth understanding of the molecular mechanisms underlying bitter taste perception. Here, we investigate the molecular determinants of the interaction of the TAS2R38 bitter taste receptor with its agonists phenylthiocarbamide (PTC) and propylthiouracil (PROP). We use the recently developed hybrid Molecular Mechanics/Coarse Grained (MM/CG) method tailored specifically for GPCRs. The method, through an extensive exploration of the conformational space in the binding pocket, allows the identification of several residues important for agonist binding that would have been very difficult to capture from the standard bioinformatics/docking approach. Our calculations suggest that both agonists bind to Asn103, Phe197, Phe264 and Trp201, whilst they do not interact with the so-called extra cellular loop 2, involved in cis-retinal binding in the GPCR rhodopsin. These predictions are consistent with data sets based on more than 20 site-directed mutagenesis and functional calcium imaging experiments of TAS2R38. The method could be readily used for other GPCRs for which experimental information is currently lacking.
authors.affiliation: International School for Advanced Studies (SISSA-ISAS), Neuroscience Sector, Trieste, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Marchiori
authors.forename: Luciana
authors.initials: L
authors.lastname: Capece
authors.forename: Alejandro
authors.initials: A
authors.lastname: Giorgetti
authors.forename: Paolo
authors.initials: P
authors.lastname: Gasparini
authors.forename: Maik
authors.initials: M
authors.lastname: Behrens
authors.forename: Paolo
authors.initials: P
authors.lastname: Carloni
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Meyerhof
mesh_terms: D019295:Computational Biology; D057809:HEK293 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D010670:Phenylthiourea / Q000737:chemistry*; D011441:Propylthiouracil / Q000737:chemistry*; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000737:chemistry* / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D012243:Rhodopsin / Q000737:chemistry; D040681:Structural Homology, Protein; D013650:Taste Buds / Q000737:chemistry; D000098706:Taste Receptors, Type 2
chemical_list: D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; D000098706:Taste Receptors, Type 2; D010670:Phenylthiourea; D011441:Propylthiouracil; D012243:Rhodopsin