Nature ( IF 42.778 ) Pub Date : 2020-09-14 , DOI: 10.1038/s41586-020-2760-4 Zaigham M. Khan; Alexander M. Real; William M. Marsiglia; Arthur Chow; Mary E. Duffy; Jayasudhan R. Yerabolu; Alex P. Scopton; Arvin C. Dar
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 oncology1, and more recently in immunotherapy2,3 and aging4. However, many MEK inhibitors (MEKi) are limited due to on-target toxicities5–7 and drug resistance8–10. 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 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.