ArticleThe Journal of biological chemistry2012
Insights into mechanism of glucokinase activation: observation of multiple distinct protein conformations.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 68 citations in OpenAlex.
- Article
- 'Intelligent' proteins.Cellular and molecular life sciences : CMLS · 2025Review
- Sugar-sensing swodkoreceptors and swodkocrine signaling.Animal models and experimental medicine · 2025Article
- In silico design of dehydrophenylalanine containing peptide activators of glucokinase using pharmacophore modelling, molecular dynamics and machine learning: implications in type 2 diabetes.Journal of computer-aided molecular design · 2024Article
- Glucokinase (GCK) in diabetes: from molecular mechanisms to disease pathogenesis.Cellular & molecular biology letters · 2024Review
- Clinical investigation of glucokinase activators for the restoration of glucose homeostasis in diabetes.Journal of diabetes · 2024Review
- Structural Analysis ofInternational journal of molecular sciences · 2023Article
- A comprehensive map of human glucokinase variant activity.Genome biology · 2023Article
- From glucose sensing to exocytosis: takes from maturity onset diabetes of the young.Frontiers in endocrinology · 2023Review
- Insights into the Genetics and Signaling Pathways in Maturity-Onset Diabetes of the Young.International journal of molecular sciences · 2022Review
- Antidiabetic Potential of Volatile Cinnamon Oil: A Review and Exploration of Mechanisms Using In Silico Molecular Docking Simulations.Molecules (Basel, Switzerland) · 2022Review
- The genetic interactions between non-alcoholic fatty liver disease and cardiovascular diseases.Frontiers in genetics · 2022Review
- Recent Advances Regarding the Physiological Functions and Biosynthesis of D-Allulose.Frontiers in microbiology · 2022Review
- The novel GCK variant p.Val455Leu associated with hyperinsulinism is susceptible to allosteric activation and is conducive to weight gain and the development of diabetes.Diabetologia · 2021Article
- Diabetic‑induced alterations in hepatic glucose and lipid metabolism: The role of type 1 and type 2 diabetes mellitus (Review).Molecular medicine reports · 2020Review
- Article
- Nanosecond-Timescale Dynamics and Conformational Heterogeneity in Human GCK Regulation and Disease.Biophysical journal · 2020Article
- Reducing Glucokinase Activity to Enhance Insulin Secretion: A Counterintuitive Theory to Preserve Cellular Function and Glucose Homeostasis.Frontiers in endocrinology · 2020Article
- Design, synthesis and evaluation of novel 3,5-disubstituted benzamide derivatives as allosteric glucokinase activators.BMC chemistry · 2019Article
- Enhanced Diffusion of Catalytically Active Enzymes.ACS central science · 2019Review
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Human glucokinase (GK) is a principal regulating sensor of plasma glucose levels. Mutations that inactivate GK are linked to diabetes, and mutations that activate it are associated with hypoglycemia. Unique kinetic properties equip GK for its regulatory role: although it has weak basal affinity for glucose, positive cooperativity in its binding of glucose causes a rapid increase in catalytic activity when plasma glucose concentrations rise above euglycemic levels. In clinical trials, small molecule GK activators (GKAs) have been efficacious in lowering plasma glucose and enhancing glucose-stimulated insulin secretion, but they carry a risk of overly activating GK and causing hypoglycemia. The theoretical models proposed to date attribute the positive cooperativity of GK to the existence of distinct protein conformations that interconvert slowly and exhibit different affinities for glucose. Here we report the respective crystal structures of the catalytic complex of GK and of a GK-glucose complex in a wide open conformation. To assess conformations of GK in solution, we also carried out small angle x-ray scattering experiments. The results showed that glucose dose-dependently converts GK from an apo conformation to an active open conformation. Compared with wild type GK, activating mutants required notably lower concentrations of glucose to be converted to the active open conformation. GKAs decreased the level of glucose required for GK activation, and different compounds demonstrated distinct activation profiles. These results lead us to propose a modified mnemonic model to explain cooperativity in GK. Our findings may offer new approaches for designing GKAs with reduced hypoglycemic risk.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.