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Determinants of human glucokinase activation and implications for small molecule allosteric control.

Authors
  • Li, Quinn1
  • Gakhar, Lokesh2
  • Ashley Spies, M3
  • 1 Department of Biochemistry, The University of Iowa, Iowa City, IA 52242, United States. , (United States)
  • 2 Department of Biochemistry, The University of Iowa, Iowa City, IA 52242, United States; Protein Crystallography Facility, The University of Iowa, Iowa City, IA 52242, United States. , (United States)
  • 3 Department of Biochemistry, The University of Iowa, Iowa City, IA 52242, United States; Department of Medicinal Natural Products Chemistry, The University of Iowa, Iowa City, IA 52242, United States. Electronic address: [email protected] , (United States)
Type
Published Article
Journal
Biochimica et Biophysica Acta (BBA) - General Subjects
Publisher
Elsevier
Publication Date
Sep 01, 2018
Volume
1862
Issue
9
Pages
1902–1912
Identifiers
DOI: 10.1016/j.bbagen.2018.06.001
PMID: 29885360
Source
Medline
Keywords
Language
English
License
Unknown

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. GK is known to undergo substantial conformational changes upon glucose binding. The monomeric enzyme possesses a highly exotic kinetic activity profile with an unusual sigmoidal dependence on glucose concentration. In this interdisciplinary study, which draws on small angle X-ray scattering (SAXS) integrated with 250 ns of atomistic molecular dynamics (MD) simulations and experimental glucose binding thermodynamics, we reveal that the critical regulation of this glucose sensor is due to a solvent controlled "switch". We demonstrate that the "solvent switch" is driven by specific protein structural dynamics, which leads to an enzyme structure that has a much more favorable solvation energy than most of the protein ensemble. These findings uncover the physical workings of an agile and flexible protein scaffold, which derives its long-range allosteric control through specific regions with favorable solvation energy. The physiological framework presented herein provides insights that 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. Copyright © 2018 Elsevier B.V. All rights reserved.

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