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首页> 外文期刊>Journal of receptor and signal transduction research >Structure-function relationships of the human bitter taste receptor hTAS2R1: Insights from molecular modeling studies
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Structure-function relationships of the human bitter taste receptor hTAS2R1: Insights from molecular modeling studies

机译：人类苦味受体hTAS2R1的结构-功能关系：分子建模研究的见解

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Bitter taste receptors (T2Rs) belong to G-protein-coupled receptors (GPCRs). Despite extensive studies, the precise mechanisms of GPCR activation are still poorly understood. In this study, the models of the human bitter taste receptor hTAS2R1 alone and in complex with various ligands were constructed on the basis of template-based modeling and molecular docking. Then these models were subjected to all-atom molecular dynamics (MD) simulations in explicit lipid bilayers. The binding pocket of hTAS2R1 is mainly formed by transmembrane helix (TM) III, TM V, TM VI, and TM VII. Most of the residues contributing to ligand binding are positionally conserved comparing with other hTAS2Rs. By comparing the final conformations obtained by extensive MD simulations, we identified the changes in the transmembrane helices and the intra- and extracellular loops, which were expected to initiate the activation of the receptor. The intracellular loop II (ICL2) and TM III were found to play prominent roles in the process of activation. We proposed that a set of interactions between the aromatic Phe115 in the middle of ICL2 and three residues (Tyr103, Lys106, and Val107) at the cytoplasmic end of TM III may serve as a conformational switch of hTAS2R1 activation. All of the residues involved in the switch are highly conserved among T2Rs. This indicates that the control switch we proposed may be universal in T2Rs. Besides, our results also suggest that the formation of a short helical segment in ICL2 may be necessary for the activation of hTAS2R1.
机译：苦味受体（T2Rs）属于G蛋白偶联受体（GPCR）。尽管进行了广泛的研究，但对GPCR激活的确切机制仍知之甚少。在这项研究中，在基于模板的建模和分子对接的基础上，构建了单独的人类苦味受体hTAS2R1以及与各种配体复合的模型。然后，这些模型在明确的脂质双层中接受全原子分子动力学（MD）模拟。 hTAS2R1的结合口袋主要由跨膜螺旋（TM）III，TMV，TMVI和TMVII形成。与其他hTAS2Rs相比，大多数有助于配体结合的残基在位置上都是保守的。通过比较广泛的MD模拟获得的最终构象，我们确定了跨膜螺旋以及细胞内和细胞外环的变化，这些变化有望启动受体的激活。发现细胞内环II（ICL2）和TM III在激活过程中起着重要作用。我们提出ICL2中间的芳香族Phe115与TM III胞质末端的三个残基（Tyr103，Lys106和Val107）之间的相互作用可以作为hTAS2R1激活的构象转换。开关中涉及的所有残基在T2R之间高度保守。这表明我们提出的控制开关在T2R中可能是通用的。此外，我们的结果还表明，ICL2中短螺旋段的形成可能是激活hTAS2R1所必需的。

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