Structural basis for the action of the drug trametinib at KSR-bound MEK

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Mitogen-activated protein kinase kinase (MEK) is a key target in oncology, immunotherapy, and aging research.
• Current MEK inhibitors face limitations due to on-target toxicities and drug resistance.
• Understanding MEK's function in physiological complexes is crucial for developing improved therapies.

Purpose of the Study:

• To elucidate the structural basis of MEK inhibition within physiological complexes.
• To investigate the binding mechanism of MEK inhibitors, including trametinib, in complex with KSR.
• To inform the design of next-generation MEK inhibitors with enhanced efficacy and reduced resistance.

Main Methods:

• X-ray crystallography was used to determine the structures of MEK bound to KSR and various MEK inhibitors.
• Analysis of drug-target interactions and binding kinetics was performed.
• Development of a novel inhibitor, trametiglue, based on structural insights.

Main Results:

• X-ray crystal structures revealed an unexpected binding mode where trametinib engages KSR at the MEK interface.
• KSR remodels the MEK inhibitor's allosteric pocket, influencing binding and drug residence time.
• Trametinib binding to KSR-MEK disrupts the related RAF-MEK complex via conserved interface residues.

Conclusions:

• The study reveals the plasticity of MEK's interface pocket and its interaction with KSR.
• The findings provide a molecular template for designing safer and more effective MEK inhibitors.
• The developed trametiglue demonstrates a strategy to limit adaptive resistance to MEK inhibition.