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The active conformation of human glucokinase is not altered by allosteric activators.

Petit P, Antoine M, Ferry G, Boutin JA, Lagarde A, Gluais L, Vincentelli R, Vuillard L
Acta Crystallogr D Biol Crystallogr 67 929-35 (2011)
Related entries: 3f9m, 3fgu, 3idh, 4no7

Cited: 28 times
EuropePMC logo PMID: 22101819

Abstract

Glucokinase (GK) catalyses the formation of glucose 6-phosphate from glucose and ATP. A specific feature of GK amongst hexokinases is that it can cycle between active and inactive conformations as a function of glucose concentration, resulting in a unique positive kinetic cooperativity with glucose, which turns GK into a unique key sensor of glucose metabolism, notably in the pancreas. GK is a target of antidiabetic drugs aimed at the activation of GK activity, leading to insulin secretion. Here, the first structures of a GK-glucose complex without activator, of GK-glucose-AMP-PNP and of GK-glucose-AMP-PNP with a bound activator are reported. All these structures are extremely similar, thus demonstrating that binding of GK activators does not result in conformational changes of the active protein but in stabilization of the active form of GK.

Articles - 3id8 mentioned but not cited (4)

  1. Mutational analysis of allosteric activation and inhibition of glucokinase. Zelent B, Odili S, Buettger C, Zelent DK, Chen P, Fenner D, Bass J, Stanley C, Laberge M, Vanderkooi JM, Sarabu R, Grimsby J, Matschinsky FM. Biochem J 440 203-215 (2011)
  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)
  3. Thermal stability of glucokinase (GK) as influenced by the substrate glucose, an allosteric glucokinase activator drug (GKA) and the osmolytes glycerol and urea. Zelent B, Buettger C, Grimsby J, Sarabu R, Vanderkooi JM, Wand AJ, Matschinsky FM. Biochim Biophys Acta 1824 769-784 (2012)
  4. Characterization of Glucokinases from Pathogenic Free-Living Amoebae. Milanes JE, Suryadi J, Monaghan NP, Harding EM, Morris CS, Rozema SD, Khalifa MM, Golden JE, Phan IQ, Zigweid R, Abendroth J, Rice CA, McCord HT, Wilson S, Fenwick MK, Morris JC. Antimicrob Agents Chemother 66 e0237321 (2022)


Reviews citing this publication (3)

  1. Essential role of conformational selection in ligand binding. Vogt AD, Pozzi N, Chen Z, Di Cera E. Biophys Chem 186 13-21 (2014)
  2. Moonlighting Proteins: The Case of the Hexokinases. Rodríguez-Saavedra C, Morgado-Martínez LE, Burgos-Palacios A, King-Díaz B, López-Coria M, Sánchez-Nieto S. Front Mol Biosci 8 701975 (2021)
  3. Mechanisms of ligand binding. Di Cera E. Biophys Rev (Melville) 1 011303 (2020)

Articles citing this publication (21)

  1. Conformational selection or induced fit? A critical appraisal of the kinetic mechanism. Vogt AD, Di Cera E. Biochemistry 51 5894-5902 (2012)
  2. Moving Beyond Active-Site Detection: MixMD Applied to Allosteric Systems. Ghanakota P, Carlson HA. J Phys Chem B 120 8685-8695 (2016)
  3. Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans. De Ceuninck F, Kargar C, Ilic C, Caliez A, Rolin JO, Umbdenstock T, Vinson C, Combettes M, de Fanti B, Harley E, Sadlo M, Lefèvre AL, Broux O, Wierzbicki M, Fourquez JM, Perron-Sierra F, Kotschy A, Ktorza A. Br J Pharmacol 168 339-353 (2013)
  4. 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)
  5. Induced Fit Is a Special Case of Conformational Selection. Chakraborty P, Di Cera E. Biochemistry 56 2853-2859 (2017)
  6. 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)
  7. Crystal structures of N-acetylmannosamine kinase provide insights into enzyme activity and inhibition. Martinez J, Nguyen LD, Hinderlich S, Zimmer R, Tauberger E, Reutter W, Saenger W, Fan H, Moniot S. J Biol Chem 287 13656-13665 (2012)
  8. 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)
  9. The use of docking-based comparative intermolecular contacts analysis to identify optimal docking conditions within glucokinase and to discover of new GK activators. Taha MO, Habash M, Khanfar MA, Khanfar MA. J Comput Aided Mol Des 28 509-547 (2014)
  10. Free Energies and Entropies of Binding Sites Identified by MixMD Cosolvent Simulations. Ghanakota P, DasGupta D, Carlson HA. J Chem Inf Model 59 2035-2045 (2019)
  11. Identification and analysis of novel R308K mutation in glucokinase of type 2 diabetic patient and its kinetic correlation. Yellapu NK, Valasani KR, Pasupuleti SK, Gopal S, Potukuchi Venkata Gurunadha Krishna S, Matcha B. Biotechnol Appl Biochem 61 572-581 (2014)
  12. Structure-based approach to the identification of a novel group of selective glucosamine analogue inhibitors of Trypanosoma cruzi glucokinase. D'Antonio EL, Deinema MS, Kearns SP, Frey TA, Tanghe S, Perry K, Roy TA, Gracz HS, Rodriguez A, D'Antonio J. Mol Biochem Parasitol 204 64-76 (2015)
  13. Role of connecting loop I in catalysis and allosteric regulation of human glucokinase. Martinez JA, Larion M, Conejo MS, Porter CM, Miller BG. Protein Sci 23 915-922 (2014)
  14. 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)
  15. 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)
  16. Discovery of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific glucokinase activators: Design, synthesis, and biological evaluation. Wang Z, Shi X, Zhang H, Yu L, Cheng Y, Zhang H, Zhang H, Zhou J, Chen J, Shen X, Duan W. Eur J Med Chem 139 128-152 (2017)
  17. Selenolysine: A New Tool for Traceless Isopeptide Bond Formation. Dardashti RN, Kumar S, Sternisha SM, Reddy PS, Miller BG, Metanis N. Chemistry 26 4952-4957 (2020)
  18. 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)
  19. Hierarchical Graph Representation of Pharmacophore Models. Arthur G, Oliver W, Klaus B, Thomas S, Gökhan I, Sharon B, Isabelle T, Pierre D, Thierry L. Front Mol Biosci 7 599059 (2020)
  20. The crystal structure of glucokinase from Leishmania braziliensis. Buechner GS, Millington ME, Perry K, D'Antonio EL. Mol Biochem Parasitol 227 47-52 (2019)
  21. 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)


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