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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Elucidating enzyme catalytic power and protein-ligand dynamics of human glucokinase: the role of modern allostery

Li, Quinn 01 July 2018 (has links)
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.

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