ArticleThe Biochemical journal2011
Mutational analysis of allosteric activation and inhibition of glucokinase.
Article in The Biochemical journal, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 32 citations in OpenAlex.
- Resetting the glucose sensor: dorzagliatin and the evolution of glucokinase activation in diabetes therapy.BMJ open diabetes research & care · 2026Review
- 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 Variant Proteins Are Resistant to Fasting-Induced Uridine Diphosphate Glucose-Dependent Degradation in Maturity-Onset Diabetes of the Young Type 2 Patients.International journal of molecular sciences · 2023Article
- Pathogenic variants of Alport syndrome and monogenic diabetes identified by exome sequencing in a family.Human genome variation · 2023Article
- Localized islet nuclear enlargement hyperinsulinism (LINE-HI) due to ABCC8 and GCK mosaic mutations.European journal of endocrinology · 2022Article
- 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
- A novel reverse two-hybrid method for the identification of missense mutations that disrupt protein-protein binding.Scientific reports · 2020Article
- Nanosecond-Timescale Dynamics and Conformational Heterogeneity in Human GCK Regulation and Disease.Biophysical journal · 2020Article
- Case 6-2020: A 34-Year-Old Woman with Hyperglycemia.The New England journal of medicine · 2020Article
- How Heterogeneity in Glucokinase and Gap-Junction Coupling Determines the Islet [CaBiophysical journal · 2019Article
- Clinical and enzymatic phenotypes in congenital hyperinsulinemic hypoglycemia due to glucokinase-activating mutations: A report of two cases and a brief overview of the literature.Journal of diabetes investigation · 2019Article
- Identification and functional analysis of GCK gene mutations in 12 Chinese families with hyperglycemia.Journal of diabetes investigation · 2019Article
- Pyridoxine dipharmacophore derivatives as potent glucokinase activators for the treatment of type 2 diabetes mellitus.Scientific reports · 2017Article
- Tryptophan Fluorescence Yields and Lifetimes as a Probe of Conformational Changes in Human Glucokinase.Journal of fluorescence · 2017Article
- Glucagon induces translocation of glucokinase from the cytoplasm to the nucleus of hepatocytes by transfer between 6-phosphofructo 2-kinase/fructose 2,6-bisphosphatase-2 and the glucokinase regulatory protein.Biochimica et biophysica acta · 2014Article
- Analysis of the co-operative interaction between the allosterically regulated proteins GK and GKRP using tryptophan fluorescence.The Biochemical journal · 2014Article
- A phospho-BAD BH3 helix activates glucokinase by a mechanism distinct from that of allosteric activators.Nature structural & molecular biology · 2014Article
- Impact of mutations on the allosteric conformational equilibrium.Journal of molecular biology · 2013Article
- GCK-MODY diabetes associated with protein misfolding, cellular self-association and degradation.Biochimica et biophysica acta · 2012Article
- Thermal stability of glucokinase (GK) as influenced by the substrate glucose, an allosteric glucokinase activator drug (GKA) and the osmolytes glycerol and urea.Biochimica et biophysica acta · 2012Article
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
GK (glucokinase) is activated by glucose binding to its substrate site, is inhibited by GKRP (GK regulatory protein) and stimulated by GKAs (GK activator drugs). To explore further the mechanisms of these processes we studied pure recombinant human GK (normal enzyme and a selection of 31 mutants) using steady-state kinetics of the enzyme and TF (tryptophan fluorescence). TF studies of the normal binary GK-glucose complex corroborate recent crystallography studies showing that it exists in a closed conformation greatly different from the open conformation of the ligand-free structure, but indistinguishable from the ternary GK-glucose-GKA complex. GKAs did activate and GKRP did inhibit normal GK, whereas its TF was doubled by glucose saturation. However, the enzyme kinetics, GKRP inhibition, TF enhancement by glucose and responsiveness to GKA of the selected mutants varied greatly. Two predominant response patterns were identified accounting for nearly all mutants: (i) GK mutants with a normal or close to normal response to GKA, normally low basal TF (indicating an open conformation), some variability of kinetic parameters (k(cat), glucose S(0.5), h and ATP K(m)), but usually strong GKRP inhibition (13/31); and (ii) GK mutants that are refractory to GKAs, exhibit relatively high basal TF (indicating structural compaction and partial closure), usually show strongly enhanced catalytic activity primarily due to lowering of the glucose S(0.5), but with reduced or no GKRP inhibition in most cases (14/31). These results and those of previous studies are best explained by envisioning a common allosteric regulator region with spatially non-overlapping GKRP- and GKA-binding sites.
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