DOI

10.17077/etd.tirid699

Document Type

Dissertation

Date of Degree

Summer 2018

Access Restrictions

Access restricted until 08/31/2020

Degree Name

PhD (Doctor of Philosophy)

Degree In

Biochemistry

First Advisor

Spies, M. Ashley

First Committee Member

Washington, M. Todd

Second Committee Member

Elcock, Adrian H.

Third Committee Member

Fuentes, Ernesto J.

Fourth Committee Member

Davies, Brandon S.

Fifth Committee Member

Roman, David L.

Abstract

Glucokinase (GK) is an enzyme that catalyzes the ATP-dependent phosphorylation of glucose to form glucose-6-phosphate, and it is a tightly regulated checkpoint in glucose homeostasis. The monomeric enzyme possesses a highly exotic kinetic profile, with a sigmoidal dependence on glucose, which has been the source of vigorous investigation and debate in the last several decades. This unique regulatory behavior can be thought of as a remarkable glucose sensor, which may result in hyperglycemia when it is not active enough and hypoglycemia when it is too active. This interdisciplinary study, which draws on small angle X-ray scattering (SAXS) integrated with atomistic molecular dynamics simulations and experimental glucose binding thermodynamics, I reveal the critical regulation of the glucose sensor is due to a solvent controlled switch. Moreover, this solvent controlled switch manifests a regulatory mechanism of GK; a specific local conformational change that leads to an enzyme structure that has a much more favorable solvation energy than most of the protein ensemble. These findings have direct implications for the design of small molecule GK activators as anti- diabetes therapeutics as well as for understanding how proteins can be designed to have built-in regulatory functions via solvation energy dynamics.

Keywords

allostery, diabetes, glucokinase, protein-solvent interactions, SAXS/MD, sensor

Pages

xiv, 124 pages

Bibliography

Includes bibliographical references (pages 21-124).

Copyright

Copyright © 2018 Quinn Li

Available for download on Monday, August 31, 2020

Included in

Biochemistry Commons

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