ArticleProceedings of the National Academy of Sciences of the United States of America2006
Conformational transition pathway in the allosteric process of human glucokinase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 80 citations in OpenAlex.
- Natural Products Beyond Inhibition: A Mechanistic Framework Spanning Pockets, Interfaces, and Kinetic Barriers.Molecules (Basel, Switzerland) · 2026Review
- Identification of residues mediating homotropic regulation in human hexokinase 3 reveals a common allosteric interface shared with hexokinase 1.Archives of biochemistry and biophysics · 2025Article
- Characterizing glucokinase variant mechanisms using a multiplexed abundance assay.Genome biology · 2024Article
- A comprehensive map of human glucokinase variant activity.Genome biology · 2023Article
- MptpA Kinetics Enhanced by Allosteric Control of an Active Conformation.Journal of molecular biology · 2022Article
- A novel reverse two-hybrid method for the identification of missense mutations that disrupt protein-protein binding.Scientific reports · 2020Article
- Conformational transition pathway of R308K mutant glucokinase in the presence of the glucokinase activator YNKGKA4.FEBS open bio · 2018Article
- Structural Features and Ligand Selectivity for 10 Intermediates in the Activation Process of βACS omega · 2017Article
- Discovery of Novel Allosteric Eg5 Inhibitors Through Structure-Based Virtual Screening.Chemical biology & drug design · 2016Article
- Human 60-kDa lysophospholipase contains an N-terminal L-asparaginase domain that is allosterically regulated by L-asparagine.The Journal of biological chemistry · 2014Article
- Analysis of the co-operative interaction between the allosterically regulated proteins GK and GKRP using tryptophan fluorescence.The Biochemical journal · 2014Article
- Mechanism of displacement of a catalytically essential loop from the active site of mammalian fructose-1,6-bisphosphatase.Biochemistry · 2013Article
- Conformational transition pathway in the activation process of allosteric glucokinase.PloS one · 2013Article
- Mutational analysis of allosteric activation and inhibition of glucokinase.The Biochemical journal · 2011Article
- Glucokinase mediates coupling of glycolysis to mitochondrial metabolism but not to beta cell damage at high glucose exposure levels.Diabetologia · 2011Article
- Binding of ATP at the active site of human pancreatic glucokinase--nucleotide-induced conformational changes with possible implications for its kinetic cooperativity.The FEBS journal · 2011Article
- Identification of 9-cis-retinoic acid as a pancreas-specific autacoid that attenuates glucose-stimulated insulin secretion.Proceedings of the National Academy of Sciences of the United States of America · 2010Article
- Endogenous activation of glucokinase by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase is glucose dependent.Molecular endocrinology (Baltimore, Md.) · 2010Article
- The energy profiles of atomic conformational transition intermediates of adenylate kinase.Proteins · 2009Article
- Structure-based predictive models for allosteric hot spots.PLoS computational biology · 2009Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Glucokinase (GK) is an important enzyme for regulating blood glucose levels and a potentially attractive target for diabetes of the young type 2 and persistent hyperinsulinemic hypoglycemia of infancy. To characterize the conformational transition of GK from the closed state to the superopen state, a series of conventional molecular dynamics (MD) and target MD (TMD) simulations were performed on both the wild-type enzyme and its mutants. Two 10-ns conventional MD simulations showed that, although the allosteric site of GK is approximately 20 A away from the active site, the activator is able to enhance the activity of the enzyme through conformational restriction. Fourteen TMD simulations on GK and five of its mutants revealed a reliably conformational transition pathway. The overall conformational transition includes three stages, and three likely stable intermediate states were identified by free energy scanning for the snapshots throughout the pathway. The conformational transition feature revealed by our TMD simulations rationalized several important mutagenesis and kinetic data. Remarkably, the TMD simulations predicted that Y61S, I159A, A201R, V203E, and V452S mutations, which have not been investigated so far, may facilitate the opening process of GK. These predictions also have been verified by mutagenesis and kinetic analyses in this study. These observations are beneficial to understanding the mechanism of GK regulation and designing the compounds for treating metabolic diseases.
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