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Structure-activity analysis of the purine binding site of human liver glycogen phosphorylase.

Ekstrom JL, Pauly TA, Carty MD, Soeller WC, Culp J, Danley DE, Hoover DJ, Treadway JL, Gibbs EM, Fletterick RJ, Day YS, Myszka DG, Rath VL
Chem Biol 9 915-24 (2002)
Related entries: 1l5q, 1l5r, 1l7x

Cited: 24 times
EuropePMC logo PMID: 12204691

Abstract

Human liver glycogen phosphorylase (HLGP) catalyzes the breakdown of glycogen to maintain serum glucose levels and is a therapeutic target for diabetes. HLGP is regulated by multiple interacting allosteric sites, each of which is a potential drug binding site. We used surface plasmon resonance (SPR) to screen for compounds that bind to the purine allosteric inhibitor site. We determined the affinities of a series of compounds and solved the crystal structures of three representative ligands with K(D) values from 17-550 microM. The crystal structures reveal that the affinities are partly determined by ligand-specific water-mediated hydrogen bonds and side chain movements. These effects could not be predicted; both crystallographic and SPR studies were required to understand the important features of binding and together provide a basis for the design of new allosteric inhibitors targeting this site.

Reviews citing this publication (9)

  1. Glycosyltransferases: structures, functions, and mechanisms. Lairson LL, Henrissat B, Davies GJ, Withers SG. Annu. Rev. Biochem. 77 521-555 (2008)
  2. New hepatic targets for glycaemic control in diabetes. Agius L. Best Pract. Res. Clin. Endocrinol. Metab. 21 587-605 (2007)
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  4. A survey of the year 2002 commercial optical biosensor literature. Rich RL, Myszka DG. J. Mol. Recognit. 16 351-382 (2003)
  5. Open challenges in structure-based virtual screening: Receptor modeling, target flexibility consideration and active site water molecules description. Spyrakis F, Cavasotto CN. Arch. Biochem. Biophys. 583 105-119 (2015)
  6. Glycogen phosphorylase inhibitors: a patent review (2008 - 2012). Gaboriaud-Kolar N, Skaltsounis AL. Expert Opin Ther Pat 23 1017-1032 (2013)
  7. NMR-Fragment Based Virtual Screening: A Brief Overview. Singh M, Tam B, Akabayov B. Molecules 23 (2018)
  8. Structural Basis for Allostery in PLP-dependent Enzymes. Tran JU, Brown BL. Front Mol Biosci 9 884281 (2022)
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Articles citing this publication (15)

  1. 5-Chloroindoloyl glycine amide inhibitors of glycogen phosphorylase: synthesis, in vitro, in vivo, and X-ray crystallographic characterization. Wright SW, Rath VL, Genereux PE, Hageman DL, Levy CB, McClure LD, McCoid SC, McPherson RK, Schelhorn TM, Wilder DE, Zavadoski WJ, Gibbs EM, Treadway JL. Bioorg. Med. Chem. Lett. 15 459-465 (2005)
  2. Binding of the potential antitumour agent indirubin-5-sulphonate at the inhibitor site of rabbit muscle glycogen phosphorylase b. Comparison with ligand binding to pCDK2-cyclin A complex. Kosmopoulou MN, Leonidas DD, Chrysina ED, Bischler N, Eisenbrand G, Sakarellos CE, Pauptit R, Oikonomakos NG. Eur. J. Biochem. 271 2280-2290 (2004)
  3. Bioactivity of glycogen phosphorylase inhibitors that bind to the purine nucleoside site. Hampson LJ, Arden C, Agius L, Ganotidis M, Kosmopoulou MN, Tiraidis C, Elemes Y, Sakarellos C, Leonidas DD, Oikonomakos NG. Bioorg. Med. Chem. 14 7835-7845 (2006)
  4. The hepatic PP1 glycogen-targeting subunit interaction with phosphorylase a can be blocked by C-terminal tyrosine deletion or an indole drug. Kelsall IR, Munro S, Hallyburton I, Treadway JL, Cohen PT. FEBS Lett. 581 4749-4753 (2007)
  5. Molecular recognition of the protein phosphatase 1 glycogen targeting subunit by glycogen phosphorylase. Pautsch A, Stadler N, Wissdorf O, Langkopf E, Moreth W, Streicher R. J Biol Chem 283 8913-8918 (2008)
  6. The crystal structure of human muscle glycogen phosphorylase a with bound glucose and AMP: an intermediate conformation with T-state and R-state features. Lukacs CM, Oikonomakos NG, Crowther RL, Hong LN, Kammlott RU, Levin W, Li S, Liu CM, Lucas-McGady D, Pietranico S, Reik L. Proteins 63 1123-1126 (2006)
  7. Binding of beta-D-glucopyranosyl bismethoxyphosphoramidate to glycogen phosphorylase b: kinetic and crystallographic studies. Chrysina ED, Kosmopoulou MN, Kardakaris R, Bischler N, Leonidas DD, Kannan T, Loganathan D, Oikonomakos NG. Bioorg. Med. Chem. 13 765-772 (2005)
  8. Advances in fragment-based drug discovery platforms. Orita M, Warizaya M, Amano Y, Ohno K, Niimi T. Expert Opin Drug Discov 4 1125-1144 (2009)
  9. Crystallographic and computational studies on 4-phenyl-N-(beta-D-glucopyranosyl)-1H-1,2,3-triazole-1-acetamide, an inhibitor of glycogen phosphorylase: comparison with alpha-D-glucose, N-acetyl-beta-D-glucopyranosylamine and N-benzoyl-N'-beta-D-glucopyranosyl urea binding. Alexacou KM, Hayes JM, Tiraidis C, Zographos SE, Leonidas DD, Chrysina ED, Archontis G, Oikonomakos NG, Paul JV, Varghese B, Loganathan D. Proteins 71 1307-1323 (2008)
  10. Sourcing the affinity of flavonoids for the glycogen phosphorylase inhibitor site via crystallography, kinetics and QM/MM-PBSA binding studies: comparison of chrysin and flavopiridol. Tsitsanou KE, Hayes JM, Keramioti M, Mamais M, Oikonomakos NG, Kato A, Leonidas DD, Zographos SE. Food Chem. Toxicol. 61 14-27 (2013)
  11. Evaluation of novel hyphodermin derivatives as glycogen phosphorylase a inhibitors. Loughlin WA, Pierens GK, Petersson MJ, Henderson LC, Healy PC. Bioorg. Med. Chem. 16 6172-6178 (2008)
  12. Synthesis and evaluation of novel oleanolic acid derivatives as potential antidiabetic agents. Zhang L, Jia X, Dong J, Chen D, Liu J, Zhang L, Wen X. Chem Biol Drug Des 83 297-305 (2014)
  13. Glycogen phosphorylase inhibitory effects of 2-oxo-1,2-dihydropyridin-3-yl amide derivatives. Karis ND, Loughlin WA, Jenkins ID, Healy PC. Bioorg. Med. Chem. 17 4724-4733 (2009)
  14. Catalysis of nucleophilic aromatic substitutions in the 2,6,8-trisubstituted purines and application in the synthesis of combinatorial libraries. Riva-Toniolo C, Müller S, Schaub J, Brill WK. Mol. Divers. 6 43-53 (2003)
  15. Synthesis, screening and docking of small heterocycles as glycogen phosphorylase inhibitors. Schweiker SS, Loughlin WA, Lohning AS, Petersson MJ, Jenkins ID. Eur J Med Chem 84 584-594 (2014)


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