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首页> 外文期刊>The FEBS journal >Identification and analysis of functionally important amino acids in human purinergic 12 receptor using a Saccharomyces cerevisiae expression system
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Identification and analysis of functionally important amino acids in human purinergic 12 receptor using a Saccharomyces cerevisiae expression system

机译：使用酿酒酵母表达系统鉴定和分析人嘌呤能12受体中功能上重要的氨基酸

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摘要

The purinergic 12 receptor (P2Y12) is a major drug target for anticoagulant therapies, but little is known about the regions involved in ligand binding and activation of this receptor. We generated four randomized P2Y12 libraries and investigated their ligand binding characteristics. P2Y12 was expressed in a Saccharomyces cerevisiae model system. Four libraries were generated with randomized amino acids at positions 181, 256, 265 and 280. Mutant variants were screened for functional activity in yeast using the natural P2Y12 ligand ADP. Activation results were investigated using quantitative structureactivity relationship (QSAR) models and ligandreceptor docking. We screened four positions in P2Y12 for functional activity by substitution with amino acids with diverse physiochemical properties. This analysis revealed that positions E181, R256 and R265 alter the functional activity of P2Y12 in a specific manner. QSAR models for E181 and R256 mutant libraries strongly supported the experimental data. All substitutions of amino acid K280 were completely inactive, highlighting the crucial role of this residue in P2Y12 function. Ligandreceptor docking revealed that K280 is likely to be a key element in the ligand-binding pocket of P2Y12. The results of this study demonstrate that positions 181, 256, 265 and 280 of P2Y12 are important for the functional integrity of the receptor. Moreover, K280 appears to be a crucial feature of the P2Y12 ligand-binding pocket. These results are important for rational design of novel antiplatelet agents.
机译：嘌呤能12受体（P2Y12）是抗凝疗法的主要药物靶标，但对与该受体的配体结合和激活有关的区域知之甚少。我们生成了四个随机的P2Y12库，并研究了它们的配体结合特征。 P2Y12在酿酒酵母模型系统中表达。产生了四个文库，分别在位置181、256、265和280具有随机氨基酸。使用天然P2Y12配体ADP筛选突变体在酵母中的功能活性。使用定量结构活性关系（QSAR）模型和配体受体对接研究了活化结果。我们通过用具有不同理化特性的氨基酸取代来筛选P2Y12中四个位置的功能活性。该分析表明，位置E181，R256和R265以特定方式改变P2Y12的功能活性。 E181和R256突变体库的QSAR模型强烈支持实验数据。氨基酸K280的所有取代都是完全无活性的，突出了该残基在P2Y12功能中的关键作用。配体受体对接揭示K280可能是P2Y12配体结合口袋中的关键元素。这项研究的结果表明，P2Y12的181、256、265和280位对于受体的功能完整性很重要。此外，K280似乎是P2Y12配体结合口袋的关键特征。这些结果对于新型抗血小板药的合理设计很重要。

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