Journal article
Determinants of human glucokinase activation and implications for small molecule allosteric control
Biochimica et biophysica acta. General subjects, Vol.1862(9), pp.1902-1912
09/2018
DOI: 10.1016/j.bbagen.2018.06.001
PMCID: PMC6051901
PMID: 29885360
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.
•Atomistic understanding of enzyme allosteric control.•Understanding the critical role of protein solvation in allosteric control.•Development of a framework for understanding glucokinase activation.
Details
- Title: Subtitle
- Determinants of human glucokinase activation and implications for small molecule allosteric control
- Creators
- Quinn Li - University of IowaLokesh Gakhar - University of IowaM Ashley Spies - Department of Biochemistry, The University of Iowa, Iowa City, IA 52242, United States
- Resource Type
- Journal article
- Publication Details
- Biochimica et biophysica acta. General subjects, Vol.1862(9), pp.1902-1912
- DOI
- 10.1016/j.bbagen.2018.06.001
- PMID
- 29885360
- PMCID
- PMC6051901
- NLM abbreviation
- Biochim Biophys Acta Gen Subj
- ISSN
- 0304-4165
- eISSN
- 1872-8006
- Publisher
- Elsevier B.V
- Grant note
- DOI: 10.13039/100006132, name: DOE Office of Science, award: DE-AC02-05CH11231; DOI: 10.13039/100006132, name: DOE Office of Science, award: DE-AC02-06CH11357; DOI: 10.13039/100000002, name: NIH, award: R01-GM097373
- Language
- English
- Date published
- 09/2018
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Biochemistry and Molecular Biology; Medicine Administration; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984293559602771
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