3vf6 › Citations

Insights into mechanism of glucokinase activation: observation of multiple distinct protein conformations.

Liu S, Ammirati MJ, Song X, Knafels JD, Zhang J, Greasley SE, Pfefferkorn JA, Qiu X
J Biol Chem 287 13598-610 (2012)
Related entries: 3vev, 3vey, 4dch, 4dhy

Cited: 36 times
EuropePMC logo PMID: 22298776

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.

Articles - 3vf6 mentioned but not cited (2)

  1. Insights into mechanism of glucokinase activation: observation of multiple distinct protein conformations. Liu S, Ammirati MJ, Song X, Knafels JD, Zhang J, Greasley SE, Pfefferkorn JA, Qiu X. J Biol Chem 287 13598-13610 (2012)
  2. Strain analysis of protein structures and low dimensionality of mechanical allosteric couplings. Mitchell MR, Tlusty T, Leibler S. Proc Natl Acad Sci U S A 113 E5847-E5855 (2016)


Reviews citing this publication (11)

  1. Solution NMR Spectroscopy for the Study of Enzyme Allostery. Lisi GP, Loria JP. Chem Rev 116 6323-6369 (2016)
  2. Molecular and cellular regulation of human glucokinase. Sternisha SM, Miller BG. Arch Biochem Biophys 663 199-213 (2019)
  3. Diabetic‑induced alterations in hepatic glucose and lipid metabolism: The role of type 1 and type 2 diabetes mellitus (Review). Jiang S, Young JL, Wang K, Qian Y, Cai L. Mol Med Rep 22 603-611 (2020)
  4. Enhanced Diffusion of Catalytically Active Enzymes. Zhang Y, Hess H. ACS Cent Sci 5 939-948 (2019)
  5. Antidiabetic Potential of Volatile Cinnamon Oil: A Review and Exploration of Mechanisms Using In Silico Molecular Docking Simulations. Stevens N, Allred K. Molecules 27 853 (2022)
  6. The genetic interactions between non-alcoholic fatty liver disease and cardiovascular diseases. Chew NWS, Chong B, Ng CH, Kong G, Chin YH, Xiao W, Lee M, Dan YY, Muthiah MD, Foo R. Front Genet 13 971484 (2022)
  7. A report of 2 new cases of MODY2 and review of the literature: implications in the search for type 2 diabetes drugs. Shammas C, Neocleous V, Phelan MM, Lian LY, Skordis N, Phylactou LA. Metabolism 62 1535-1542 (2013)
  8. A Comprehensive Review of Novel Drug-Disease Models in Diabetes Drug Development. Gaitonde P, Garhyan P, Link C, Chien JY, Trame MN, Schmidt S. Clin Pharmacokinet 55 769-788 (2016)
  9. Recent Advances Regarding the Physiological Functions and Biosynthesis of D-Allulose. Chen Z, Gao XD, Li Z. Front Microbiol 13 881037 (2022)
  10. Insights into the Genetics and Signaling Pathways in Maturity-Onset Diabetes of the Young. Sousa M, Rego T, Armas JB. Int J Mol Sci 23 12910 (2022)
  11. From glucose sensing to exocytosis: takes from maturity onset diabetes of the young. Samadli S, Zhou Q, Zheng B, Gu W, Zhang A. Front Endocrinol (Lausanne) 14 1188301 (2023)

Articles citing this publication (23)

  1. Order-disorder transitions govern kinetic cooperativity and allostery of monomeric human glucokinase. Larion M, Salinas RK, Bruschweiler-Li L, Miller BG, Brüschweiler R. PLoS Biol 10 e1001452 (2012)
  2. A phospho-BAD BH3 helix activates glucokinase by a mechanism distinct from that of allosteric activators. Szlyk B, Braun CR, Ljubicic S, Patton E, Bird GH, Osundiji MA, Matschinsky FM, Walensky LD, Danial NN. Nat Struct Mol Biol 21 36-42 (2014)
  3. The catalytic inactivation of the N-half of human hexokinase 2 and structural and biochemical characterization of its mitochondrial conformation. Nawaz MH, Ferreira JC, Nedyalkova L, Zhu H, Carrasco-López C, Kirmizialtin S, Rabeh WM. Biosci Rep 38 BSR20171666 (2018)
  4. Analysis of the co-operative interaction between the allosterically regulated proteins GK and GKRP using tryptophan fluorescence. Zelent B, Raimondo A, Barrett A, Buettger CW, Chen P, Gloyn AL, Matschinsky FM. Biochem J 459 551-564 (2014)
  5. Reducing Glucokinase Activity to Enhance Insulin Secretion: A Counterintuitive Theory to Preserve Cellular Function and Glucose Homeostasis. Whitticar NB, Nunemaker CS. Front Endocrinol (Lausanne) 11 378 (2020)
  6. A Common Gene Variant in Glucokinase Regulatory Protein Interacts With Glucose Metabolism on Diabetic Dyslipidemia: the Combined CODAM and Hoorn Studies. Simons N, Dekker JM, van Greevenbroek MM, Nijpels G, 't Hart LM, van der Kallen CJ, Schalkwijk CG, Schaper NC, Stehouwer CD, Brouwers MC. Diabetes Care 39 1811-1817 (2016)
  7. Acyl-ACP substrate recognition in Burkholderia mallei BmaI1 acyl-homoserine lactone synthase. Montebello AN, Brecht RM, Turner RD, Ghali M, Pu X, Nagarajan R. Biochemistry 53 6231-6242 (2014)
  8. Ligand-based modeling followed by in vitro bioassay yielded new potent glucokinase activators. Taha MO, Habash M, Hatmal MM, Abdelazeem AH, Qandil A. J Mol Graph Model 56 91-102 (2015)
  9. A comprehensive map of human glucokinase variant activity. Gersing S, Cagiada M, Gebbia M, Gjesing AP, Coté AG, Seesankar G, Li R, Tabet D, Weile J, Stein A, Gloyn AL, Hansen T, Roth FP, Lindorff-Larsen K, Hartmann-Petersen R. Genome Biol 24 97 (2023)
  10. Nitric Oxide Activates β-Cell Glucokinase by Promoting Formation of the "Glucose-Activated" State. Seckinger KM, Rao VP, Snell NE, Mancini AE, Markwardt ML, Rizzo MA. Biochemistry 57 5136-5144 (2018)
  11. QSAR Models Guided by Molecular Dynamics Applied to Human Glucokinase Activators. de Assis TM, Gajo GC, de Assis LC, Garcia LS, Silva DR, Ramalho TC, da Cunha EF. Chem Biol Drug Des 87 455-466 (2016)
  12. Structural insight into the glucokinase-ligands interactions. Molecular docking study. Ermakova E. Comput Biol Chem 64 281-296 (2016)
  13. 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. Langer S, Waterstradt R, Hillebrand G, Santer R, Baltrusch S. Diabetologia 64 2687-2700 (2021)
  14. Plasmodium vivax and human hexokinases share similar active sites but display distinct quaternary architectures. Srivastava SS, Darling JE, Suryadi J, Morris JC, Drew ME, Subramaniam S. IUCrJ 7 453-461 (2020)
  15. A new compound heterozygosis for inactivating mutations in the glucokinase gene as cause of permanent neonatal diabetes mellitus (PNDM) in double-first cousins. Esquiaveto-Aun AM, De Mello MP, Paulino MF, Minicucci WJ, Guerra-Júnior G, De Lemos-Marini SH. Diabetol Metab Syndr 7 101 (2015)
  16. Small-Molecule Allosteric Activation of Human Glucokinase in the Absence of Glucose. Bowler JM, Hervert KL, Kearley ML, Miller BG. ACS Med Chem Lett 4 (2013)
  17. Nanosecond-Timescale Dynamics and Conformational Heterogeneity in Human GCK Regulation and Disease. Sternisha SM, Whittington AC, Martinez Fiesco JA, Porter C, McCray MM, Logan T, Olivieri C, Veglia G, Steinbach PJ, Miller BG. Biophys J 118 1109-1118 (2020)
  18. Tryptophan Fluorescence Yields and Lifetimes as a Probe of Conformational Changes in Human Glucokinase. Zelent B, Bialas C, Gryczynski I, Chen P, Chib R, Lewerissa K, Corradini MG, Ludescher RD, Vanderkooi JM, Matschinsky FM. J Fluoresc 27 1621-1631 (2017)
  19. Design, synthesis and evaluation of novel 3,5-disubstituted benzamide derivatives as allosteric glucokinase activators. Grewal AS, Kharb R, Prasad DN, Dua JS, Lather V. BMC Chem 13 2 (2019)
  20. Structure based design, synthesis and biological evaluation of amino phosphonate derivatives as human glucokinase activators. Yellapu NK, Kilaru RB, Chamarthi N, Pvgk S, Matcha B. Comput Biol Chem 68 118-130 (2017)
  21. ¹⁹F nuclear magnetic resonance screening of glucokinase activators. Assemat O, Antoine M, Fourquez JM, Wierzbicki M, Charton Y, Hennig P, Perron-Sierra F, Ferry G, Boutin JA, Delsuc MA. Anal Biochem 477 62-68 (2015)
  22. Determinants of human glucokinase activation and implications for small molecule allosteric control. Li Q, Gakhar L, Ashley Spies M. Biochim Biophys Acta Gen Subj 1862 1902-1912 (2018)
  23. Structural Analysis of Plasmodium falciparum Hexokinase Provides Novel Information about Catalysis Due to a Plasmodium-Specific Insertion. Dillenberger M, Werner AD, Velten AS, Rahlfs S, Becker K, Fritz-Wolf K. Int J Mol Sci 24 12739 (2023)


Quick links