Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view.
Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view.
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DOI：
10.1039/c5cs00911a
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发表时间：
2016-09-21
影响因子：
46.2
通讯作者：
Nussinov R
中科院分区：
文献类型：
--
作者：
Lu S;Jang H;Gu S;Zhang J;Nussinov R
Ras蛋白是小的GTP酶，在非活性GDP结合和活性GTP结合状态之间循环。通过这些开关，它们调节控制细胞生长和增殖的信号。激活Ras突变与大约30%的人类癌症相关，这些癌症通常对标准疗法具有抗性。在过去的几年里，结构生物学和计算机药物设计，加上改进的筛选技术，导致了一些有前途的抑制剂，提高了对Ras蛋白进行药物治疗的可能性。与此同时，耐药性的不断出现证明了额外磨练可能参与的信号通路的至关重要性。本文综述了Ras结构方面的最新进展，包括全长Ras在溶液和膜上的构象动力学，通过靶向其活性位点、变构位点和Ras效应蛋白-蛋白界面来抑制Ras活性，Ras二聚体，K-Ras 4 B/钙调蛋白/PI 3 K α三聚体，以及siRNA靶向Ras。为了减轻耐药性，我们提出了可以与Ras共同靶向的信号通路，并解释了原因。这些包括导致YAP 1和c-Myc表达（或激活）的途径。我们推测这些信号通路和Ras信号通路MAPK/ERK和PI 3 K/Akt/mTOR在细胞周期控制中独立地并以相应的方式起作用。结构数据有助于发现和开发用于治疗RAS驱动的癌症的Ras抑制剂。连同耐药性可以进化的信号蓝图，这篇综述为解决突变Ras蛋白提供了一个全面和创新的总体规划。在这篇综述中，我们概述了目前的进展，Ras的结构知识和信号通路，可以共同作为目标沿着Ras，以减轻耐药性。
Ras proteins are small GTPases, cycling between inactive GDP-bound and active GTP-bound states. Through these switches they regulate signaling that controls cell growth and proliferation. Activating Ras mutations are associated with approximately 30% of human cancers, which are frequently resistant to standard therapies. Over the past few years, structural biology and in silico drug design, coupled with improved screening technology, led to a handful of promising inhibitors, raising the possibility of drugging Ras proteins. At the same time, the invariable emergence of drug resistance argues for the critical importance of additionally honing in on signaling pathways which are likely to be involved. Here we overview current advances in Ras structural knowledge, including the conformational dynamic of full-length Ras in solution and at the membrane, therapeutic inhibition of Ras activity by targeting its active site, allosteric sites, and Ras–effector protein-protein interfaces, Ras dimers, the K-Ras4B/calmodulin/PI3Kα trimer, and targeting Ras with siRNA. To mitigate drug resistance, we propose signaling pathways that can be co-targeted along with Ras and explain why. These include pathways leading to the expression (or activation) of YAP1 and c-Myc. We postulate that these and Ras signaling pathways, MAPK/ERK and PI3K/Akt/mTOR, act independently and in corresponding ways in cell cycle control. The structural data are instrumental in the discovery and development of Ras inhibitors for treating RAS-driven cancers. Together with the signaling blueprints through which drug resistance can evolve, this review provides a comprehensive and innovative master plan for tackling mutant Ras proteins. In this review we overview current advances in Ras structural knowledge and the signaling pathways that can be co-targeted along with Ras to mitigate drug resistance.
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DOI：
10.1038/nrm3255
发表时间：
2011-12-22
期刊：
Nature reviews. Molecular cell biology
影响因子：
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作者：
通讯作者：
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影响因子：
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作者：
Arozarena, Imanol;Calvo, Fernando;Crespo, Piero
通讯作者：
Crespo, Piero
影响因子：
64.8
作者：
Boussemart, Lise;Malka-Mahieu, Helene;Vagner, Stephan
通讯作者：
Vagner, Stephan
影响因子：
30.8
作者：
Bell, DW;Gore, I;Haber, DA
通讯作者：
Haber, DA
DOI：
10.4161/cc.7.17.6596
发表时间：
2008-09-01
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Abankwa D;Gorfe AA;Hancock JF
通讯作者：
Hancock JF