Structural basis for the action of the drug trametinib at KSR-bound MEK.
Structural basis for the action of the drug trametinib at KSR-bound MEK.
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trametinib在KSR结合的MEK中作用的结构性基础。
DOI：
10.1038/s41586-020-2760-4
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发表时间：
2020-12
期刊：
影响因子：
64.8
通讯作者：
Dar AC
中科院分区：
文献类型：
--
作者：
Khan ZM;Real AM;Marsiglia WM;Chow A;Duffy ME;Yerabolu JR;Scopton AP;Dar AC
MAPK/ERK Kinase MEK是常见的癌症驱动因素KRAS和BRAF的共同效应器，长期以来，KRAS和BRAF一直是肿瘤学以及最近在免疫治疗和衰老领域的药物靶点。然而，许多MEK抑制剂(MEKI)由于靶向毒性和耐药性而受到限制。因此，对生理复合体中MEK结构和功能的分子理解可以为设计更安全和更有效的治疗方法提供模板。在这里，我们报道了包括临床药物曲美替尼在内的各种Meki与支架KSR(RAS的激酶抑制因子)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，在这种模式下，曲美替尼在MEK界面直接与KSR结合。通过络合作用，KSR重塑了典型的Meki变构口袋，从而影响了结合和动力学，包括药物停留时间。此外，曲美替尼与KSR-MEK结合，但通过一种利用进化保守的界面残基区分这些亚复合体的机制来破坏相关的RAF-MEK复合体。基于这些见解，我们创造了曲美替胶，通过增强界面结合来限制对Meki的适应性抵抗。综上所述，我们的结果揭示了MEK亚复合体中界面口袋的可塑性，这对设计针对RAS途径的下一代药物具有重要意义。
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, and more recently in immunotherapy and aging. However, many MEK inhibitors (MEKi) are limited due to on-target toxicities and drug resistance. 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 MEKi, including the clinical drug trametinib. The structures reveal an unexpected mode of binding in which trametinib directly engages KSR at the MEK interface. Through complexation, KSR remodels the prototypical MEKi allosteric pocket thereby impacting binding and kinetics, including 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 subcomplexes. Based on these insights we created trametiglue, which limits adaptive resistance to MEKi through enhanced interfacial binding. Together, our results reveal the plasticity of an interface pocket within MEK subcomplexes that has implications for the design of next generation drugs targeting the RAS pathway.
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影响因子：
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作者：
Brennan, Damian F.;Dar, Arvin C.;Barford, David
通讯作者：
Barford, David