ArticlePLoS biology2012
Order-disorder transitions govern kinetic cooperativity and allostery of monomeric human glucokinase.
Article in PLoS biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 68 citations in OpenAlex.
- Quantitative assessment of porin-mediated solute transport in biomimetic membranes.Applied microbiology and biotechnology · 2025Article
- N-terminal domain of polypyrimidine-tract binding protein is a dynamic folding platform for adaptive RNA recognition.Nucleic acids research · 2024Article
- Characterizing glucokinase variant mechanisms using a multiplexed abundance assay.Genome biology · 2024Article
- The disordered C-terminal tail of fungal LPMOs from phytopathogens mediates protein dimerization and impacts plant penetration.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- A comprehensive map of human glucokinase variant activity.Genome biology · 2023Article
- Biochemical methods to map and quantify allosteric motions in human glucokinase.Methods in enzymology · 2023Article
- Bioinformatic Analysis of Lytic Polysaccharide Monooxygenases Reveals the Pan-Families Occurrence of Intrinsically Disordered C-Terminal Extensions.Biomolecules · 2021Article
- Flash properties of Gaussia luciferase are the result of covalent inhibition after a limited number of cycles.Protein science : a publication of the Protein Society · 2021Article
- A hexokinase isoenzyme switch in human liver cancer cells promotes lipogenesis and enhances innate immunity.Communications biology · 2021Article
- Nanosecond-Timescale Dynamics and Conformational Heterogeneity in Human GCK Regulation and Disease.Biophysical journal · 2020Article
- Tuning Allostery through Integration of Disorder to Order with a Residue Network.Biochemistry · 2020Article
- Propagation of the Allosteric Signal in Phosphofructokinase fromBiochemistry · 2019Article
- Molecular and cellular regulation of human glucokinase.Archives of biochemistry and biophysics · 2019Review
- Nitric Oxide Activates β-Cell Glucokinase by Promoting Formation of the "Glucose-Activated" State.Biochemistry · 2018Article
- Molecular analysis of human Ero1 reveals novel regulatory mechanisms for oxidative protein folding.Life science alliance · 2018Article
- Mechanistic Origins of Enzyme Activation in Human Glucokinase Variants Associated with Congenital Hyperinsulinism.Biochemistry · 2018Article
- Biochemical and biophysical investigations of the interaction between human glucokinase and pro-apoptotic BAD.PloS one · 2017Article
- Order, Disorder, and Everything in Between.Molecules (Basel, Switzerland) · 2016Review
- Solution NMR Spectroscopy for the Study of Enzyme Allostery.Chemical reviews · 2016Review
- Regulation of Glucokinase by Intracellular Calcium Levels in Pancreatic β Cells.The Journal of biological chemistry · 2016Article
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
Glucokinase (GCK) catalyzes the rate-limiting step of glucose catabolism in the pancreas, where it functions as the body's principal glucose sensor. GCK dysfunction leads to several potentially fatal diseases including maturity-onset diabetes of the young type II (MODY-II) and persistent hypoglycemic hyperinsulinemia of infancy (PHHI). GCK maintains glucose homeostasis by displaying a sigmoidal kinetic response to increasing blood glucose levels. This positive cooperativity is unique because the enzyme functions exclusively as a monomer and possesses only a single glucose binding site. Despite nearly a half century of research, the mechanistic basis for GCK's homotropic allostery remains unresolved. Here we explain GCK cooperativity in terms of large-scale, glucose-mediated disorder-order transitions using 17 isotopically labeled isoleucine methyl groups and three tryptophan side chains as sensitive nuclear magnetic resonance (NMR) probes. We find that the small domain of unliganded GCK is intrinsically disordered and samples a broad conformational ensemble. We also demonstrate that small-molecule diabetes therapeutic agents and hyperinsulinemia-associated GCK mutations share a strikingly similar activation mechanism, characterized by a population shift toward a more narrow, well-ordered ensemble resembling the glucose-bound conformation. Our results support a model in which GCK generates its cooperative kinetic response at low glucose concentrations by using a millisecond disorder-order cycle of the small domain as a "time-delay loop," which is bypassed at high glucose concentrations, providing a unique mechanism to allosterically regulate the activity of human GCK under physiological conditions.
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