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Document Type

Campus-Only Access for Five (5) Years

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Molecular and Cellular Biology

Year Degree Awarded

2018

Month Degree Awarded

September

First Advisor

Scott C Garman

Subject Categories

Biochemistry | Structural Biology

Abstract

Acid α-glucosidase (GAA) is required for the degradation of lysosomal glycogen. Pompe disease is an autosomal recessive disorder caused by reduced GAA activity, resulting in the accumulation of glycogen within lysosomes. The most severe form of the disease is characterized by a progressive deterioration of cardiac and skeletal muscle leading to death before two years of age. An intense interest from both the academic and pharmaceutical communities led us to determine the crystal structure of GAA. The structure provides insight into Pompe disease by examining how over 200 disease-associated point mutations perturb GAA function. To aid in the development of therapeutic approaches for Pompe disease, the structural basis for ligand binding and the catalytic mechanism were studied. The work identified a second ligand binding site distant from the active site leading to a new model of the GAA:glycogen complex. This second ligand binding site maybe useful for developing pharmacological chaperones that do not inhibit the active site. Additionally, the structures identify key interactions between GAA and NB-DNJ, a pharmacological chaperone currently in clinical trials, and identifies modifications that maybe useful for improving active site directed pharmacological chaperones for Pompe disease.

Available for download on Friday, March 01, 2019

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