Insights into the binding of agonist and antagonist to TAS2R16 receptor: a molecular simulation study

Chen, Zhirong; Dong, Shifen; Meng, Fancui; Liang, Yaoyue; Zhang, Shuofeng; Sun, Jing

doi:10.1080/08927022.2017.1376325

Cited by 9 publications

(8 citation statements)

References 28 publications

(25 reference statements)

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“…1), we suggest that the solution to this apparent dichotomy is the existence of a previously unrecognized dual binding mode. Unlike previously published models (see Supplementary Text S2 55,67 , our findings can provide a molecular explanation to all the available experimental data, even if the mutagenesis data were not used to drive the docking or bias the simulations. Moreover, they provide a rationale for the SAR data 53–56 and thus give insights applicable to other hTAS2R16 agonists, besides the three studied here.…”

Section: Discussionmentioning

confidence: 75%

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Dual binding mode of “bitter sugars” to their human bitter taste receptor target

Fierro

Giorgetti

Carloni

et al. 2019

Sci Rep

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The 25 human bitter taste receptors (hTAS2Rs) are responsible for detecting bitter molecules present in food, and they also play several physiological and pathological roles in extraoral compartments. Therefore, understanding their ligand specificity is important both for food research and for pharmacological applications. Here we provide a molecular insight into the exquisite molecular recognition of bitter β-glycopyranosides by one of the members of this receptor subclass, hTAS2R16. Most of its agonists have in common the presence of a β-glycopyranose unit along with an extremely structurally diverse aglycon moiety. This poses the question of how hTAS2R16 can recognize such a large number of “bitter sugars”. By means of hybrid molecular mechanics/coarse grained molecular dynamics simulations, here we show that the three hTAS2R16 agonists salicin, arbutin and phenyl-β-D-glucopyranoside interact with the receptor through a previously unrecognized dual binding mode. Such mechanism may offer a seamless way to fit different aglycons inside the binding cavity, while maintaining the sugar bound, similar to the strategy used by several carbohydrate-binding lectins. Our prediction is validated a posteriori by comparison with mutagenesis data and also rationalizes a wealth of structure-activity relationship data. Therefore, our findings not only provide a deeper molecular characterization of the binding determinants for the three ligands studied here, but also give insights applicable to other hTAS2R16 agonists. Together with our results for other hTAS2Rs, this study paves the way to improve our overall understanding of the structural determinants of ligand specificity in bitter taste receptors.

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Section: Discussionmentioning

confidence: 75%

“…Subsequently, Chen et al . 67 presented a second model of the receptor in complex with salicin, using a computational approach similar to Sakurai, followed by molecular dynamics. Unfortunately, also this prediction seems not to be consistent with all the available mutagenesis data.…”

Section: Introductionmentioning

confidence: 99%

Dual binding mode of “bitter sugars” to their human bitter taste receptor target

Fierro

Giorgetti

Carloni

et al. 2019

Sci Rep

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“…Since the crystal structures of TAS2Rs have not been determined, most previous studies of TAS2Rligand interactions are based on models simulated by the structure of other GPCRs (e.g. human b2 adrenergic receptor and bovine rhodopsin) [33][34][35]. Thus, arbutin may facilitate analyses of the crystal structure of the well-studied bitter taste receptor TAS2R16.…”

Section: Discussionmentioning

confidence: 99%

A natural point mutation in the bitter taste receptor TAS2R16 causes inverse agonism of arbutin in lemur gustation

et al. 2019

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Bitter taste enables the detection of potentially harmful substances and is mediated by bitter taste receptors, TAS2Rs, in vertebrates. Few antagonists and inverse agonists of TAS2Rs have been identified, especially natural compounds. TAS2R16s in humans, apes and Old World monkeys (Catarrhini, Anthropoidea) recognize β-glucoside analogues as specific agonists. Here, we investigated responses of TAS2R16 to β-glucosides in non-anthropoid primates, namely lemurs (Lemuriformes, Strepsirrhini). Salicin acted as an agonist on lemur TAS2R16. Arbutin acted as an agonist in the ring-tailed lemur ( Lemur catta ) but as an inverse agonist in black lemur ( Eulemur macaco ) and black-and-white ruffed lemur ( Varecia variegata ). We identified a strepsirrhine-specific amino acid substitution responsible for the inverse agonism of arbutin. In a food preference test, salicin bitterness was inhibited by arbutin in the black lemur. Structural modelling revealed this locus was important for a rearrangement of the intracellular end of transmembrane helix 7 (TM7). Accordingly, arbutin is the first known natural inverse agonist of TAS2Rs, contributing to our understanding of receptor–ligand interactions and the molecular basis of the unique feeding habit diversification in lemurs. Furthermore, the identification of a causal point mutation suggests that TAS2R can acquire functional changes according to feeding habits and environmental conditions.

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“…This is particularly important for GPCR models based on low sequence identity, as it is the case for chemosensory receptors, where the low accuracy of the side chain prediction and the limited sampling of the docking algorithms may undermine the quality of the bioinformatics-based models. There are several studies in the literature applying molecular dynamics simulations to chemosensory receptors (Gelis et al, 2012; Lai and Crasto, 2012; Charlier et al, 2013; Lai et al, 2014; Chen et al, 2018; Jaggupilli et al, 2018; Liu et al, 2018; Bushdid et al, 2019). Here we focus on a hybrid, multiscale approach developed in our group (Neri et al, 2005, 2008; Leguèbe et al, 2012; Giorgetti and Carloni, 2014; Musiani et al, 2015; Tarenzi et al, 2017), which is tailored to study ligand binding in GPCRs.…”

Section: Methodsmentioning

confidence: 99%

Understanding Ligand Binding to G-Protein Coupled Receptors Using Multiscale Simulations

Alfonso‐Prieto

Navarini²,

Carloni

2019

Front. Mol. Biosci.

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Human G-protein coupled receptors (GPCRs) convey a wide variety of extracellular signals inside the cell and they are one of the main targets for pharmaceutical intervention. Rational drug design requires structural information on these receptors; however, the number of experimental structures is scarce. This gap can be filled by computational models, based on homology modeling and docking techniques. Nonetheless, the low sequence identity across GPCRs and the chemical diversity of their ligands may limit the quality of these models and hence refinement using molecular dynamics simulations is recommended. This is the case for olfactory and bitter taste receptors, which constitute the first and third largest GPCR groups and show sequence identities with the available GPCR templates below 20%. We have developed a molecular dynamics approach, based on the combination of molecular mechanics and coarse grained (MM/CG), tailored to study ligand binding in GPCRs. This approach has been applied so far to bitter taste receptor complexes, showing significant predictive power. The protein/ligand interactions observed in the simulations were consistent with extensive mutagenesis and functional data. Moreover, the simulations predicted several binding residues not previously tested, which were subsequently verified by carrying out additional experiments. Comparison of the simulations of two bitter taste receptors with different ligand selectivity also provided some insights into the binding determinants of bitter taste receptors. Although the MM/CG approach has been applied so far to a limited number of GPCR/ligand complexes, the excellent agreement of the computational models with the mutagenesis and functional data supports the applicability of this method to other GPCRs for which experimental structures are missing. This is particularly important for the challenging case of GPCRs with low sequence identity with available templates, for which molecular docking shows limited predictive power.

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Insights into the binding of agonist and antagonist to TAS2R16 receptor: a molecular simulation study

Cited by 9 publications

References 28 publications

Dual binding mode of “bitter sugars” to their human bitter taste receptor target

Dual binding mode of “bitter sugars” to their human bitter taste receptor target

A natural point mutation in the bitter taste receptor TAS2R16 causes inverse agonism of arbutin in lemur gustation

Understanding Ligand Binding to G-Protein Coupled Receptors Using Multiscale Simulations

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