The MAPK/ERK kinase MEK is a shared effector of the frequent cancer drivers KRAS and BRAF that has long been pursued as a drug target in oncology 1 , and more recently in immunotherapy 2 , 3 and ageing 4 . However, many MEK inhibitors are limited owing to on-target toxicities 5 – 7 and drug resistance 8 – 10 . Accordingly, a molecular understanding of the structure and function of MEK within physiological complexes could provide a template for the design of safer and more effective therapies. Here we report X-ray crystal structures of MEK bound to the scaffold KSR (kinase suppressor of RAS) with various MEK inhibitors, including the clinical drug trametinib. The structures reveal an unexpected mode of binding in which trametinib directly engages KSR at the MEK interface. In the bound complex, KSR remodels the prototypical allosteric pocket of the MEK inhibitor, thereby affecting binding and kinetics, including the drug-residence time. Moreover, trametinib binds KSR–MEK but disrupts the related RAF–MEK complex through a mechanism that exploits evolutionarily conserved interface residues that distinguish these sub-complexes. On the basis of these insights, we created trametiglue, which limits adaptive resistance to MEK inhibition by enhancing interfacial binding. Our results reveal the plasticity of an interface pocket within MEK sub-complexes and have implications for the design of next-generation drugs that target the RAS pathway. Crystal structures of the MEK kinase bound to the scaffold protein KSR and various MEK inhibitors, including the anti-cancer drug trametinib, reveal the molecular and functional mechanisms behind MEK inhibition.

中文翻译：

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药物曲美替尼对 KSR 结合的 MEK 作用的结构基础

MAPK/ERK 激酶 MEK 是常见的癌症驱动因子 KRAS 和 BRAF 的共同效应物，长期以来一直作为肿瘤学 1 的药物靶点，最近在免疫治疗 2、3 和衰老 4 中被追求。然而，由于靶向毒性 5 – 7 和耐药性 8 – 10，许多 MEK 抑制剂受到限制。因此，对生理复合物中 MEK 的结构和功能的分子理解可以为设计更安全、更有效的疗法提供模板。在这里，我们报告了使用各种 MEK 抑制剂（包括临床药物曲美替尼）与支架 KSR（RAS 激酶抑制剂）结合的 MEK 的 X 射线晶体结构。这些结构揭示了一种意想不到的结合模式，其中曲美替尼在 MEK 界面直接与 KSR 结合。在绑定复合体中，KSR 重塑了 MEK 抑制剂的原型变构袋，从而影响结合和动力学，包括药物停留时间。此外，曲美替尼与 KSR-MEK 结合，但通过利用进化上保守的界面残基区分这些亚复合物的机制破坏相关的 RAF-MEK 复合物。基于这些见解，我们创建了曲美胶，它通过增强界面结合来限制对 MEK 抑制的适应性抗性。我们的结果揭示了 MEK 子复合物中界面袋的可塑性，并对设计靶向 RAS 通路的下一代药物产生了影响。MEK激酶的晶体结构与支架蛋白KSR和各种MEK抑制剂结合，包括抗癌药trametinib，