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Covalent Inhibitors Allosterically Block the Activation of Rho Family Proteins and Suppress Cancer Cell Invasion.
Advanced Science ( IF 14.3 ) Pub Date : 2020-05-13 , DOI: 10.1002/advs.202000098 Zhongya Sun 1 , Hao Zhang 2 , Yuanyuan Zhang 2 , Liping Liao 2, 3 , Wen Zhou 4 , Fengcai Zhang 2, 5 , Fulin Lian 2 , Jing Huang 2, 3 , Pan Xu 2, 3 , Rukang Zhang 2, 3 , Wenchao Lu 2, 3 , Mingrui Zhu 2, 3 , Hongru Tao 2 , Feng Yang 2, 6 , Hong Ding 2 , Shijie Chen 2 , Liyan Yue 2 , Bing Zhou 2 , Naixia Zhang 2 , Minjia Tan 2 , Hualiang Jiang 2 , Kaixian Chen 2, 6, 7 , Bo Liu 4, 8 , Chuanpeng Liu 1 , Yongjun Dang 9 , Cheng Luo 2, 3, 10, 11
Advanced Science ( IF 14.3 ) Pub Date : 2020-05-13 , DOI: 10.1002/advs.202000098 Zhongya Sun 1 , Hao Zhang 2 , Yuanyuan Zhang 2 , Liping Liao 2, 3 , Wen Zhou 4 , Fengcai Zhang 2, 5 , Fulin Lian 2 , Jing Huang 2, 3 , Pan Xu 2, 3 , Rukang Zhang 2, 3 , Wenchao Lu 2, 3 , Mingrui Zhu 2, 3 , Hongru Tao 2 , Feng Yang 2, 6 , Hong Ding 2 , Shijie Chen 2 , Liyan Yue 2 , Bing Zhou 2 , Naixia Zhang 2 , Minjia Tan 2 , Hualiang Jiang 2 , Kaixian Chen 2, 6, 7 , Bo Liu 4, 8 , Chuanpeng Liu 1 , Yongjun Dang 9 , Cheng Luo 2, 3, 10, 11
Affiliation
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The Rho family GTPases are crucial drivers of tumor growth and metastasis. However, it is difficult to develop GTPases inhibitors due to a lack of well‐characterized binding pockets for compounds. Here, through molecular dynamics simulation of the RhoA protein, a groove around cysteine 107 (Cys107) that is relatively well‐conserved within the Rho family is discovered. Using a combined strategy, the novel inhibitor DC‐Rhoin is discovered, which disrupts interaction of Rho proteins with guanine nucleotide exchange factors (GEFs) and guanine nucleotide dissociation inhibitors (GDIs). Crystallographic studies reveal that the covalent binding of DC‐Rhoin to the Cys107 residue stabilizes and captures a novel allosteric pocket. Moreover, the derivative compound DC‐Rhoin04 inhibits the migration and invasion of cancer cells, through targeting this allosteric pocket of RhoA. The study reveals a novel allosteric regulatory site within the Rho family, which can be exploited for anti‐metastasis drug development, and also provides a novel strategy for inhibitor discovery toward “undruggable” protein targets.
中文翻译：
共价抑制剂变构阻断 Rho 家族蛋白的激活并抑制癌细胞侵袭。
Rho 家族 GTP 酶是肿瘤生长和转移的关键驱动因素。然而，由于缺乏充分表征的化合物结合口袋，开发 GTP 酶抑制剂很困难。在这里，通过对RhoA蛋白的分子动力学模拟，发现了Rho家族中相对保守的半胱氨酸107（Cys107）周围的凹槽。采用组合策略，发现了新型抑制剂 DC-Rhoin，它破坏 Rho 蛋白与鸟嘌呤核苷酸交换因子 (GEF) 和鸟嘌呤核苷酸解离抑制剂 (GDI) 的相互作用。晶体学研究表明，DC-Rhoin 与 Cys107 残基的共价结合可稳定并捕获新的变构袋。此外，衍生化合物 DC-Rhoin04 通过靶向 RhoA 的变构袋来抑制癌细胞的迁移和侵袭。该研究揭示了 Rho 家族中的一个新的变构调节位点，可用于抗转移药物的开发，并且还为发现“不可成药”蛋白质靶标的抑制剂提供了一种新策略。
更新日期：2020-07-22
中文翻译：
共价抑制剂变构阻断 Rho 家族蛋白的激活并抑制癌细胞侵袭。
Rho 家族 GTP 酶是肿瘤生长和转移的关键驱动因素。然而，由于缺乏充分表征的化合物结合口袋，开发 GTP 酶抑制剂很困难。在这里，通过对RhoA蛋白的分子动力学模拟，发现了Rho家族中相对保守的半胱氨酸107（Cys107）周围的凹槽。采用组合策略，发现了新型抑制剂 DC-Rhoin，它破坏 Rho 蛋白与鸟嘌呤核苷酸交换因子 (GEF) 和鸟嘌呤核苷酸解离抑制剂 (GDI) 的相互作用。晶体学研究表明，DC-Rhoin 与 Cys107 残基的共价结合可稳定并捕获新的变构袋。此外，衍生化合物 DC-Rhoin04 通过靶向 RhoA 的变构袋来抑制癌细胞的迁移和侵袭。该研究揭示了 Rho 家族中的一个新的变构调节位点，可用于抗转移药物的开发，并且还为发现“不可成药”蛋白质靶标的抑制剂提供了一种新策略。
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