Crystal structure of E339K mutated human glucokinase reveals changes in the ATP binding site

Liu, Qiang; Shen, Yue; Liu, Sanling; Weng, Jianping; Liu, Jinsong

doi:10.1016/j.febslet.2011.03.026

Cited by 6 publications

(3 citation statements)

References 23 publications

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“…As mentioned, Src is a non-receptor tyrosine kinase. Glucokinase is reported to contain serine phosphorylation sites, but not tyrosine 38,39 , and glucokinase has not been considered as a substrate of Src 7,40-42 . Because interaction of Src with glucokinase was not observed by immunoprecipitation (data not shown), Src is not likely to interact with glucokinase directly.…”

Section: Discussionmentioning

confidence: 99%

Src regulates insulin secretion and glucose metabolism by influencing subcellular localization of glucokinase in pancreatic β‐cells

Sato

Nagashima

Ogura

et al. 2015

J of Diabetes Invest

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Aims/IntroductionSrc, a non‐receptor tyrosine kinase, regulates a wide range of cellular functions, and hyperactivity of Src is involved in impaired glucose metabolism in pancreatic β‐cells. However, the physiological role of Src in glucose metabolism in normal, unstressed β‐cells remains unclear. In the present study, we investigated the role of Src in insulin secretion and glucose metabolism.Materials and MethodsSrc was downregulated using small interfering ribonucleic acid in INS‐1 cells, and glucose‐induced insulin secretion, adenosine triphosphate content, intracellular calcium concentration, glucose utilization and glucokinase activity were measured. Expression levels of messenger ribonucleic acid and protein of glucokinase were examined by semiquantitative real‐time polymerase chain reaction and immunoblotting, respectively. Cells were fractionated by digitonin treatment, and subcellular localization of glucokinase was examined by immunoblotting. Interaction between glucokinase and neuronal nitric oxide synthase was estimated by immunoprecipitation.ResultsIn Src downregulated INS‐1 cells, glucose‐induced insulin secretion was impaired, whereas insulin secretion induced by high K+ was not affected. Intracellular adenosine triphosphate content and elevation of intracellular calcium concentration by glucose stimulation were suppressed by Src downregulation. Src downregulation reduced glucose utilization in the presence of high glucose, which was accompanied by a reduction in glucokinase activity without affecting its expression. However, Src downregulation reduced glucokinase in soluble, cytoplasmic fraction, and increased it in pellet containing intaracellular organelles. In addition, interaction between glucokinase and neuronal nitric oxide synthase was facilitated by Src downregulation.ConclusionsSrc plays an important role in glucose‐induced insulin secretion in pancreatic β‐cells through maintaining subcellular localization and activity of glucokinase.

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Section: Discussionmentioning

confidence: 99%

Src regulates insulin secretion and glucose metabolism by influencing subcellular localization of glucokinase in pancreatic β‐cells

Sato

Nagashima

Ogura

et al. 2015

J of Diabetes Invest

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“…Predicted pockets using DoGSiteScorer for Hexokinase IV in complex with α-D-glucose only (PDB ID: 3QIC (34)). An ensemble was generated with SIENA using 3QIC as query structure and α-D-glucose as reference ligand.…”

Section: The Proteinsplus Servermentioning

confidence: 99%

ProteinsPlus: a web portal for structure analysis of macromolecules

Fährrolfes

Bietz

Flachsenberg

et al. 2017

Nucleic Acids Research

182

116

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With currently more than 126 000 publicly available structures and an increasing growth rate, the Protein Data Bank constitutes a rich data source for structure-driven research in fields like drug discovery, crop science and biotechnology in general. Typical workflows in these areas involve manifold computational tools for the analysis and prediction of molecular functions. Here, we present the ProteinsPlus web server that offers a unified easy-to-use interface to a broad range of tools for the early phase of structure-based molecular modeling. This includes solutions for commonly required pre-processing tasks like structure quality assessment (EDIA), hydrogen placement (Protoss) and the search for alternative conformations (SIENA). Beyond that, it also addresses frequent problems as the generation of 2D-interaction diagrams (PoseView), protein–protein interface classification (HyPPI) as well as automatic pocket detection and druggablity assessment (DoGSiteScorer). The unified ProteinsPlus interface covering all featured approaches provides various facilities for intuitive input and result visualization, case-specific parameterization and download options for further processing. Moreover, its generalized workflow allows the user a quick familiarization with the different tools. ProteinsPlus also stores the calculated results temporarily for future request and thus facilitates convenient result communication and re-access. The server is freely available at http://proteins.plus.

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“…These investigators also successfully determined the structure of unliganded glucokinase, albeit at a much lower resolution of 3.4 Å. Since that initial report, ten additional crystal structures of human glucokinase have been reported [86–94]. With these structures, data is presently available for several complexes formed along the reaction coordinate, including the binary enzyme-glucose complex, as well as the ternary complex formed between enzyme, glucose and a non-hydrolyzable ATP analog.…”

Section: Structural Bases For Allosteric Transitions In Glucokinasementioning

confidence: 99%

Homotropic allosteric regulation in monomeric mammalian glucokinase

Larion

Miller

2012

Archives of Biochemistry and Biophysics

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Glucokinase catalyzes the ATP-dependent phosphorylation of glucose, a chemical transformation that represents the rate-limiting step of glycolytic metabolism in the liver and pancreas. Glucokinase is a central regulator of glucose homeostasis as evidenced by its association with two disease states, maturity onset diabetes of the young (MODY) and persistent hyperinsulinemia of infancy (PHHI). Mammalian glucokinase is subject to homotropic allosteric regulation by glucose — the steady-state velocity of glucose 6-phosphate production is not hyperbolic, but instead displays a sigmoidal response to increasing glucose concentrations. The positive cooperativity displayed by glucokinase is intriguing since the enzyme functions as a monomer under physiological conditions and contains only a single binding site for glucose. Despite the existence of several models of kinetic cooperativity in monomeric enzymes, a consensus has yet to be reached regarding the mechanism of allosteric regulation in glucokinase. Experimental evidence collected over the last 45 years by a number of investigators supports a link between cooperativity and slow conformational reorganizations of the glucokinase scaffold. In this review, we summarize advances in our understanding of glucokinase allosteric regulation resulting from recent X-ray crystallographic, pre-equilibrium kinetic and high-resolution nuclear magnetic resonance investigations. We conclude with a brief discussion of unanswered questions regarding the mechanistic basis of kinetic cooperativity in mammalian glucokinase.

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Crystal structure of E339K mutated human glucokinase reveals changes in the ATP binding site

Cited by 6 publications

References 23 publications

Src regulates insulin secretion and glucose metabolism by influencing subcellular localization of glucokinase in pancreatic β‐cells

Src regulates insulin secretion and glucose metabolism by influencing subcellular localization of glucokinase in pancreatic β‐cells

ProteinsPlus: a web portal for structure analysis of macromolecules

Homotropic allosteric regulation in monomeric mammalian glucokinase

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