Date of Award

Spring 2025

Document Type

Restricted Thesis

Terms of Use

© 2025 Aaron Thammavongxay. All rights reserved. Access to this work is restricted to users within the Swarthmore College network and may only be used for non-commercial, educational, and research purposes. Sharing with users outside of the Swarthmore College network is expressly prohibited. For all other uses, including reproduction and distribution, please contact the copyright holder.

Degree Name

Bachelor of Arts

Department

Chemistry & Biochemistry Department

First Advisor

Daniela Fera

Abstract

The mitogen activated protein kinase (MAPK) signaling pathway is involved in a variety of cellular processes ranging from proliferation to differentiation to apoptosis. Dysfunction of the pathway is implicated in a range of human cancers which makes regulation of the pathway an attractive therapeutic target. Mutations often occur in proteins upstream in the pathway which serve as common targets for drug therapies; however, such approaches are limited by drug resistance. MEK and ERK kinase are downstream effectors of the pathway and have a highly specific interaction that could serve as an alternative target for pathway regulation. Allosteric methods of inhibition can lend greater drug specificity compared to conventional therapies. Yet, the exact details of the MEK-ERK interaction remain unclear as no high-resolution structure of the MEKERK complex exists.

We aimed to characterize potential models of MEK-ERK interaction by identifying residues involved in binding using experimental and computational methods. We generated complexes of MEK and ERK using computational docking and AlphaFold3 to identify residues implicated in binding and used sequence alignments to identify conserved residues likely implicated in binding. We mutated residues of interest and characterized changes in binding affinity using biolayer interferometry. We identified MEK residues L235, E312, L314, and K362E as potentially involved in binding. We also determine ERK-L234 is implicated in a hydrophobic pocket with MEK-L235 and L314.

Future work can utilize this information to stabilize the MEK-ERK complex through mutagenesis for use in structural studies that might elucidate a complete experimental structure of the complex.

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