Targeting the α4-α5 interface of RAS results in multiple levels of inhibition.
Targeting the α4-α5 interface of RAS results in multiple levels of inhibition.
复制标题
靶向 RAS 的α4-α5 界面会导致多级抑制。
DOI：
10.1080/21541248.2017.1333188
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
O'Bryan,JohnP
中科院分区：
文献类型：
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作者：
Spencer-Smith,Russell;Li,Lie;Prasad,Sheela;Koide,Akiko;Koide,Shohei;O'Bryan,JohnP
RAS靶向疗法的产生一直被认为是癌症研究中的“圣杯”。然而，RAS表面上缺乏结合口袋及其对鸟嘌呤核苷酸的皮摩尔亲和力使得抑制剂的分离特别具有挑战性。我们最近描述了一种称为NS 1的单抗体，其阻断RAS信号传导和致癌转化。NS 1结合H-RAS和K-RAS的α4-β6-α5界面，从而阻止RAS二聚化和纳米簇，这反过来又阻止RAS刺激的RAF二聚化和活化。有趣的是，NS 1减少了致癌K-RAS（而不是H-RAS）与RAF的相互作用，并减少了K-RAS质膜定位。在这里，我们表明，这些亚型的具体影响NS 1 RAS：RAF是由于不同的高变区的RAS亚型。NS 1通过降低RAS GTP水平抑制野生型RAS功能。这些发现表明，NS 1通过一种比简单地抑制RAS二聚化和纳米簇更复杂的机制破坏RAS信号传导。
Generation of RAS-targeted therapeutics has long been considered a “holy grail” in cancer research. However, a lack of binding pockets on the surface of RAS and its picomolar affinity for guanine nucleotides have made isolation of inhibitors particularly challenging. We recently described a monobody, termed NS1, that blocks RAS signaling and oncogenic transformation. NS1 binds to the α4-β6-α5 interface of H-RAS and K-RAS thus preventing RAS dimerization and nanoclustering, which in turn prevents RAS-stimulated dimerization and activation of RAF. Interestingly, NS1 reduces interaction of oncogenic K-RAS, but not H-RAS, with RAF and reduces K-RAS plasma membrane localization. Here, we show that these isoform specific effects of NS1 on RAS:RAF are due to the distinct hypervariable regions of RAS isoforms. NS1 inhibited wild type RAS function by reducing RAS GTP levels. These findings reveal that NS1 disrupts RAS signaling through a mechanism that is more complex than simply inhibiting RAS dimerization and nanoclustering.