Date of Award

Spring 2023

Document Type

Restricted Thesis

Terms of Use

© 2023 Sabrina Lin. 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


Chemistry & Biochemistry Department

First Advisor

Daniela Fera


MEK and ERK kinases are part of the MAPK signaling pathway. This pathway is crucial for a variety of processes such as cell proliferation, differentiation, and cell death. Many mutations occur in proteins upstream of MEK and ERK that lead to various diseases such as melanomas and drug resistance has made existing drugs ineffective. Because of this, we want to better understand the interactions between proteins downstream in this pathway such as MEK and ERK to see if there are allosteric sites that can be potential drug targets. Allosteric sites are of interest, because allosteric inhibitors have better selectivity and have shown to develop drug resistance less frequently in comparison to other types of inhibitors.

One of the most direct ways to understand how two proteins interact is to elucidate a structure of their complex. In order to do structural studies, the stability of the MEK and ERK complex had to be assessed. Coelution studies showed that MEK and ERK have a weak interaction. To strengthen their interaction, various methods were attempted, but they were either unsuccessful or required further optimization.

Thus, to study the complex, we obtained theoretical models of the complex through computational docking to determine which regions in MEK and ERK could be important for their interaction. From these generated models, we identified possible residues at the MEK-ERK binding interface, mutated them, and expressed these mutant proteins. We then used biolayer interferometry (BLI) and phosphorylation assays to determine the effects of these ERK mutations on binding and phosphorylation by MEK. Results from these experiments suggested that residues K114 and K270 may not be important to the MEK and ERK interaction, but residue K231 could potentially be.

Computational docking can be repeated with this updated information to obtain more accurate models. Further work can be done to strengthen and stabilize the MEK and ERK complex to work towards elucidating a structure of their complex. This in conjunction with computational docking and biochemical studies can help work towards a more accurate model of the complex.