Kinetic Basis of Carbohydrate-Mediated Inhibition of Human Glucokinase by the Glucokinase Regulatory Protein

Casey, Ashley K.; Miller, Brian G.

doi:10.1021/acs.biochem.6b00349

Cited by 5 publications

(2 citation statements)

References 26 publications

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“…[54] Recent kinetic and mutational work suggest that the differential effects of these ligands upon complex stability are dictated by the conformational state of the flexible N-terminus. [55,56] Ligands that favor an extended N-terminus poise GKRP for optimal coulombic interactions with residues located near the hinge region of GCK. Conversely, ligands that favor a more compact N-terminus disrupt these stabilizing interactions and weaken the protein-protein interaction.…”

Section: Inhibition Of Gck By the Glucokinase Regulatory Proteinmentioning

confidence: 99%

Molecular and cellular regulation of human glucokinase

Sternisha

Miller

2019

Archives of Biochemistry and Biophysics

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104

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Glucose metabolism in humans is tightly controlled by the activity of glucokinase (GCK). GCK is predominantly produced in the pancreas, where it catalyzes the rate-limiting step of insulin secretion, and in hepatocytes, where it participates in glycogen synthesis. A multitude of diseasecausing mutations within the gck gene have been identified. Activating mutations manifest themselves in the clinic as congenital hyperinsulinism, while loss-of-function mutations produce several diabetic conditions. Indeed, pharmaceutical companies have shown great interest in developing GCK-associated treatments for diabetic patients. Due to its essential role in maintaining whole-body glucose homeostasis, GCK activity is extensively regulated at multiple levels. GCK possesses a unique ability to self-regulate its own activity via slow conformational dynamics, which allows for a cooperative response to glucose. GCK is also subject to a number of protein-protein interactions and post-translational modification events that produce a broad range of physiological consequences. While significant advances in our understanding of these individual regulatory mechanisms have been recently achieved, how these strategies are integrated and coordinated within the cell is less clear. This review serves to synthesize the relevant findings and offer insights into the connections between molecular and cellular control of GCK.

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Section: Inhibition Of Gck By the Glucokinase Regulatory Proteinmentioning

confidence: 99%

Molecular and cellular regulation of human glucokinase

Sternisha

Miller

2019

Archives of Biochemistry and Biophysics

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104

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“…A minimum of five individual binding traces were collected on a logarithmic scale until equilibrium was reached (0.005–20 s) for each AMG-3969 concentration. Binding traces were analyzed and fit to a sum of exponentials equation using the software provided by the manufacturer as previously described, , to yield rate constants and amplitudes for each AMG-3969 concentration. When present, the concentration of fructose 6-phosphate was 2 mM.…”

Section: Methodsmentioning

confidence: 99%

Antidiabetic Disruptors of the Glucokinase−Glucokinase Regulatory Protein Complex Reorganize a Coulombic Interface

et al. 2017

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The glucokinase regulatory protein (GKRP) plays an essential role in glucose homeostasis by acting as a competitive inhibitor of glucokinase (GCK) and triggering its localization to the hepatocyte nucleus upon glucose deprivation. Metabolites such as fructose 6-phosphate and sorbitol 6-phosphate promote assembly of the GCK-GKRP complex, whereas fructose 1-phosphate and functionalized piperazines with potent in vivo antidiabetic activity disrupt the complex. Here, we establish the molecular basis by which these natural and synthetic ligands modulate the GCK-GKRP interaction. We demonstrate that a small-molecule disruptor of the protein-protein interaction utilizes a two-step conformational selection mechanism to associate with a rare GKRP conformation constituting 3% of the total population. Conformational heterogeneity of GKRP is localized to the N-terminus and deleting this region eliminates the ability of sorbitol 6-phosphate to promote the GCK-GKRP interaction. Stabilizing ligands favor an extended N-terminus, which sterically positions two arginine residues for optimal coulombic interaction with a pair of carboxylate side chains from GCK. Conversely, disruptors promote a more compact N-terminus in which an interfacial arginine residue is stabilized in an unproductive orientation through a cation-π interaction with tyrosine 75. Eliminating the ability to sample this binding impaired conformation enhances the intrinsic inhibitory activity of GKRP. Elucidating the molecular basis of ligand-mediated control over the GCK-GKRP interaction is expected to impact the development and future refinement of therapeutic agents for diabetes and cardiovascular disease, which result from improper GKRP regulation of GCK.

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Characterization of Glucokinase Catalysis from a Pseudo-Dimeric View

Chen

Cai

et al. 2019

Appl Biochem Biotechnol

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Kinetic Basis of Carbohydrate-Mediated Inhibition of Human Glucokinase by the Glucokinase Regulatory Protein

Cited by 5 publications

References 26 publications

Molecular and cellular regulation of human glucokinase

Molecular and cellular regulation of human glucokinase

Antidiabetic Disruptors of the Glucokinase−Glucokinase Regulatory Protein Complex Reorganize a Coulombic Interface

Characterization of Glucokinase Catalysis from a Pseudo-Dimeric View

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