Honors Theses

Date of Award


Document Type

Undergraduate Thesis


Chemistry and Biochemistry

First Advisor

Susan Pedigo

Relational Format



Classical cadherins are a subfamily of calcium-dependent cellular adhesion molecules that play an important role in the formation of cellular junctions in many tissues. The extracellular portion of cadherins consists of five tandem-repeated domains (EC1-EC5). The critical first step in cadherin-mediated cellular adhesion occurs at the interface between two adjacent EC1 domains in which the transition from monomer to dimer is accomplished by docking the W2 residue of the N-terminal β-strand of one EC1 domain into the hydrophobic pocket of its partner domain. Cancer and many other diseases have been linked to the aberrant expression of Epithelial (E-cad) and Neural Cadherins (N- cad). Due to the importance of cadherins in the study of cancer, the hydrophobic pocket of the EC1 domain is of interest because it provides a possible site for the selective inhibition of dimerization as an anti-cancer treatment. Furthermore, if the shape of the hydrophobic pocket is different in E-cad and N-cad, then perhaps these differences may be exploited to target a specific tissue or specific form of cancer. In order to study the significance of the hydrophobic pocket, we studied the crystal structures of the EC1-EC2 domains of E-cad and N-cad using the imaging software Chimera. First, we compared the position of critical hydrophobic pocket residues in two identical crystal structures of N- cad and likewise for E-cad. Second, we used a specific function in Chimera to obtain area and volume measurements of the hydrophobic pocket and its opening in each structure. Subsequently, a database of indole derivatives were docked into the hydrophobic pocket using the software OpenEye to identify potential ligands that could selectively bind a single Cadherin subtype. Results indicate that there is indeed a difference in the size and shape of the hydrophobic pockets of N-cad and E-cad that leads to differences in the optimal indole derivatives predicted to bind to N-cad and E-cad. These critical results suggest that the hydrophobic pockets of these two proteins are different and may be exploited for selective inhibition of dimerization by cadherin subtypes. Future studies will be directed toward developing these unique indole structures as possible cancer therapies.

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