The RAS GTPases are frequently mutated in human cancer, with KRAS being the predominant tumor driver. For many years, it has been known that the structure and function of RAS are integrally linked, as structural changes induced by GTP binding or mutational events determine the ability of RAS to interact with regulators and effectors. Recently, a wealth of information has emerged from structures of specific KRAS mutants and from structures of multiprotein complexes containing RAS and/or RAF, an essential effector of RAS. These structures provide key insights regarding RAS and RAF regulation as well as promising new strategies for therapeutic intervention. Significance: The RAS GTPases are major drivers of tumorigenesis, and for RAS proteins to exert their full oncogenic potential, they must interact with the RAF kinases to initiate ERK cascade signaling. Although binding to RAS is typically a prerequisite for RAF to become an activated kinase, determining the molecular mechanisms by which this interaction results in RAF activation has been a challenging task. A major advance in understanding this process and RAF regulation has come from recent structural studies of various RAS and RAF multiprotein signaling complexes, revealing new avenues for drug discovery.

中文翻译：

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结构胜千言：RAS 和 RAF 监管的新见解


RAS GTP 酶在人类癌症中经常发生突变，其中 KRAS 是主要的肿瘤驱动因素。多年来，人们知道 RAS 的结构和功能是紧密相连的，因为 GTP 结合或突变事件引起的结构变化决定了 RAS 与调节因子和效应因子相互作用的能力。最近，从特定 KRAS 突变体的结构以及包含 RAS 和/或 RAF（RAS 的重要效应子）的多蛋白复合物的结构中出现了大量信息。这些结构提供了有关 RAS 和 RAF 调节的重要见解以及有前景的治疗干预新策略。意义：RAS GTPases 是肿瘤发生的主要驱动因素，为了使 RAS 蛋白充分发挥其致癌潜力，它们必须与 RAF 激酶相互作用以启动 ERK 级联信号传导。尽管与 RAS 的结合通常是 RAF 成为激活激酶的先决条件，但确定这种相互作用导致 RAF 激活的分子机制一直是一项具有挑战性的任务。最近对各种 RAS 和 RAF 多蛋白信号复合物的结构研究在理解这一过程和 RAF 调控方面取得了重大进展，揭示了药物发现的新途径。