Hamamura-Yasuno Eri, Matsushita Junya, Sato Seiji, Shimada Takashi, Tsuchiya Yoshimi, Fujimoto Kazunori, Mori Kazuhiko
Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo, 134-8630, Japan.
Modality Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.
Sci Rep. 2022 Apr 22;12(1):6650. doi: 10.1038/s41598-022-10549-6.
MAS-related G protein-coupled receptor X2 (MRGPRX2), expressed in human mast cells, is associated with drug-induced pseudo-allergic reactions. Dogs are highly sensitive to the anaphylactoid reactions induced by certain drugs including fluoroquinolones. Recently, dog MRGPRX2 was identified as a functional ortholog of human MRGPRX2, with dog MRGPRX2 being particularly sensitive to fluoroquinolones. The aim of this study was to determine key residues responsible for the enhanced activity of fluoroquinolone-induced histamine release associated with MRGPRX2. Firstly, a structure model of human and dog MRGPRX2 was built by homology modeling, and docking simulations with fluoroquinolones were conducted. This model indicated that E164 and D184, conserved between human and dog, are essential for the binding to fluoroquinolones. In contrast, F78 (dog: Y) and M109 (dog: W) are unconserved residues, to which the species difference in fluoroquinolone sensitivity is attributable. Intracellular calcium mobilisation assay with human MRGPRX2 mutants, in which residues at positions 78 and 109 were substituted to those of dog MRGPRX2, revealed that M109 and F78 of human MRGPRX2 are crucial residues for enhancing the fluoroquinolone-induced histamine release. In conclusion, these key residues have important clinical implications for revealing the mechanisms and predicting the risks of fluoroquinolone-mediated pseudo-allergic reactions in humans.
与MAS相关的G蛋白偶联受体X2（MRGPRX2）在人类肥大细胞中表达，与药物诱导的假性过敏反应有关。犬类对包括氟喹诺酮类在内的某些药物诱导的类过敏反应高度敏感。最近，犬类MRGPRX2被鉴定为人类MRGPRX2的功能直系同源物，犬类MRGPRX2对氟喹诺酮类特别敏感。本研究的目的是确定与MRGPRX2相关的氟喹诺酮诱导组胺释放增强活性的关键残基。首先，通过同源建模构建了人类和犬类MRGPRX2的结构模型，并进行了与氟喹诺酮类的对接模拟。该模型表明，人类和犬类之间保守的E164和D184对于与氟喹诺酮类的结合至关重要。相比之下，F78（犬类：Y）和M109（犬类：W）是不保守的残基，氟喹诺酮敏感性的物种差异可归因于此。对人类MRGPRX2突变体进行细胞内钙动员测定，其中第78和109位的残基被替换为犬类MRGPRX2的残基，结果表明人类MRGPRX2的M109和F78是增强氟喹诺酮诱导组胺释放的关键残基。总之，这些关键残基对于揭示人类氟喹诺酮介导的假性过敏反应的机制和预测风险具有重要的临床意义。
