G protein-coupled receptors (GPCRs) have always been important drug targets in the pharmaceutical industry. One major question for the current GPCR drug discovery is how drugs have distinct efficacies at the same GPCR target. Related to this question, we studied how different ligands can have disparate efficacies at Leukotriene B₄ receptor (BLT2). By using molecular modeling studies, we predicted that Tyr271^6.51 located at TM6 of BLT2 performs as a key trigger for its activation and verified the prediction by site-directed mutagenesis, chemotactic motility studies, which included a chemical derivative of agonist CAY10583. We further identified Asn275^6.55 located at TM6 as a weak activation trigger in BLT2 and performed double mutation studies to confirm our computational results. Our results provide strong evidence for the exact mechanism of ligand efficacy at BLT2.

中文翻译：

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阐明白三烯 B4 受体 2 (BLT2) 配体功效的机制。

G 蛋白偶联受体 (GPCR) 一直是制药行业的重要药物靶点。当前 GPCR 药物发现的一个主要问题是药物如何在相同的 GPCR 靶点上具有不同的功效。与这个问题相关，我们研究了不同的配体如何对白三烯 B ₄受体 (BLT2)产生不同的功效。通过使用分子建模研究，我们预测位于BLT2 TM6 的Tyr271 ^6.51是其激活的关键触发因素，并通过定点诱变、趋化运动研究验证了预测，其中包括激动剂 CAY10583 的化学衍生物。我们进一步确定了 Asn275 ^6.55位于 TM6 作为 BLT2 中的弱激活触发器并进行双突变研究以确认我们的计算结果。我们的结果为 BLT2 配体功效的确切机制提供了强有力的证据。