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7JUT

Crystal Structure of KSR2:MEK1 in complex with ANP-PNP, and allosteric MEK inhibitor Selumetinib

Summary for 7JUT
Entry DOI10.2210/pdb7jut/pdb
Related7JUQ 7JUR 7JUS 7JUU 7JUV 7JUW 7JUX 7JUY 7JUZ 7JV0 7JV1
DescriptorKinase suppressor of Ras 2, Dual specificity mitogen-activated protein kinase kinase 1, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (5 entities in total)
Functional Keywordskinase, pseudokinase, drug target, cell signaling and cancer, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
Biological sourceHomo sapiens (Human)
More
Total number of polymer chains2
Total formula weight84338.17
Authors
Khan, Z.M.,Dar, A.C. (deposition date: 2020-08-20, release date: 2020-09-30, Last modification date: 2023-10-18)
Primary citationKhan, Z.M.,Real, A.M.,Marsiglia, W.M.,Chow, A.,Duffy, M.E.,Yerabolu, J.R.,Scopton, A.P.,Dar, A.C.
Structural basis for the action of the drug trametinib at KSR-bound MEK.
Nature, 588:509-514, 2020
Cited by
PubMed Abstract: 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 ageing. However, many MEK inhibitors are limited owing 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 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.
PubMed: 32927473
DOI: 10.1038/s41586-020-2760-4
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (3.09 Å)
Structure validation

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