Date

2017

Department or Program

Biological Chemistry

Primary Wellesley Thesis Advisor

David Haines

Additional Advisor(s)

Melissa Beers

Additional Advisor

Adrian Huang

Additional Advisor

Larry Rosenwald

Abstract

The glucagon-like peptide-1 receptor (GLP-1R) is implicated in the pancreatic signaling pathway responsible for insulin secretion. Due to its seven transmembrane domains, a nuanced model of the GLP-1R structure cannot be elucidated through X-ray crystallography. We intend to improve current understanding of GLP-1R structure and binding mechanisms by chemically modifying T-0632, one of its non-peptide small molecule antagonists, in order to alter its interactions with the GLP-1R active site. To accomplish this, we will produce an analog of T-0632 in which an amine group is inserted at the standard carboxylic acid locus. In doing so, we will disrupt charged interactions between T-0632 and the extracellular loops of GLP-1R; these interactions are suspected of producing the inhibitory effect in bound T-0632.

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