化学抑制促进转移的赖氨酰-tRNA 合成酶-层粘连蛋白受体相互作用。
Chemical inhibition of prometastatic lysyl-tRNA synthetase-laminin receptor interaction.
机构信息
1] Medicinal Bioconvergence Research Center, Seoul National University, Seoul, Korea. [2] Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea. [3].
1] Medicinal Bioconvergence Research Center, Seoul National University, Seoul, Korea. [2] Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea.
出版信息
Nat Chem Biol. 2014 Jan;10(1):29-34. doi: 10.1038/nchembio.1381. Epub 2013 Nov 10.
Lysyl-tRNA synthetase (KRS), a protein synthesis enzyme in the cytosol, relocates to the plasma membrane after a laminin signal and stabilizes a 67-kDa laminin receptor (67LR) that is implicated in cancer metastasis; however, its potential as an antimetastatic therapeutic target has not been explored. We found that the small compound BC-K-YH16899, which binds KRS, impinged on the interaction of KRS with 67LR and suppressed metastasis in three different mouse models. The compound inhibited the KRS-67LR interaction in two ways. First, it directly blocked the association between KRS and 67LR. Second, it suppressed the dynamic movement of the N-terminal extension of KRS and reduced membrane localization of KRS. However, it did not affect the catalytic activity of KRS. Our results suggest that specific modulation of a cancer-related KRS-67LR interaction may offer a way to control metastasis while avoiding the toxicities associated with inhibition of the normal functions of KRS.
赖氨酰-tRNA 合成酶（KRS）是细胞质中的一种蛋白质合成酶，在层粘连蛋白信号作用下转移到质膜，并稳定参与癌症转移的 67kDa 层粘连蛋白受体（67LR）；然而，其作为抗转移治疗靶点的潜力尚未得到探索。我们发现，与 KRS 结合的小分子化合物 BC-K-YH16899 可干扰 KRS 与 67LR 的相互作用，并在三种不同的小鼠模型中抑制转移。该化合物通过两种方式抑制 KRS-67LR 相互作用。首先，它直接阻断 KRS 与 67LR 的结合。其次，它抑制 KRS N 端延伸的动态运动，减少 KRS 的膜定位。然而，它不影响 KRS 的催化活性。我们的结果表明，对与癌症相关的 KRS-67LR 相互作用的特异性调节可能提供一种控制转移的方法，同时避免抑制 KRS 正常功能相关的毒性。
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