Crystallographic studies on α- and β-D-glucopyranosyl formamide analogues, inhibitors of glycogen phosphorylase

E. D. Chrysina, N. G. Oikonomakos, S. E. Zographos, M. N. Kosmopoulou, N. Bischler, D. D. Leonidas, L. Kovács, T. Docsa, P. Gergely, L. Somsák

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

The catalytic site of glycogen phosphorylase (GP) is currently under investigation as a target for inhibition of hepatic glycogenolysis under high glucose conditions. Three D-glucopyranosyl analogues, C-(1-azido-α-D-glucopyranosyl) formamide, C-(1-acetamido-α-D-glucopyranosyl) formamide, and C-(1-hydroxy-β-D-glucopyranosyl) formamide, were recognised as moderate competitive inhibitors of muscle glycogen phosphorylase b (GPb) [with respect to α-D-glucose 1-phosphate (Glc-l-P)] with Ki values of 1.80 (±0.2) mM, 0.31 (±0.01) mM, and 0.88 (±0.04) mM, respectively. In order to elucidate the structural basis of inhibition, we determined the structure of muscle GPb complexed with the three compounds at 2.1, 2.06 and 2.0 Å resolution, respectively. The complex structures revealed that the inhibitors can be accommodated in the catalytic site of T-state GPb with very little change of the tertiary structure, and provide a rationalisation for understanding potency of the inhibitors. The glucopyranose moiety makes the standard hydrogen bonds and van der Waals contacts as observed in the GPb-glucose complex, while the substituent groups in the α- and β-position of the C1 atom make additional hydrogen bonding and van der Waals interactions to the protein.

Original languageEnglish
Pages (from-to)233-242
Number of pages10
JournalBiocatalysis and Biotransformation
Volume21
Issue number4-5
DOIs
Publication statusPublished - Aug 2003

Fingerprint

Glycogen Phosphorylase
Phosphorylase b
Glucose
Muscle
Catalytic Domain
Hydrogen bonds
Glycogenolysis
Muscles
Hydrogen Bonding
Hydrogen
Phosphates
formamide
Glycogen
Proteins
Atoms
Liver

Keywords

  • Glucopyranosyl formamides
  • Glycogen phosphorylates
  • Inhibitor
  • Type 2 diabetes
  • X-ray crystallography

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Biotechnology
  • Catalysis

Cite this

Crystallographic studies on α- and β-D-glucopyranosyl formamide analogues, inhibitors of glycogen phosphorylase. / Chrysina, E. D.; Oikonomakos, N. G.; Zographos, S. E.; Kosmopoulou, M. N.; Bischler, N.; Leonidas, D. D.; Kovács, L.; Docsa, T.; Gergely, P.; Somsák, L.

In: Biocatalysis and Biotransformation, Vol. 21, No. 4-5, 08.2003, p. 233-242.

Research output: Contribution to journalArticle

Chrysina, E. D. ; Oikonomakos, N. G. ; Zographos, S. E. ; Kosmopoulou, M. N. ; Bischler, N. ; Leonidas, D. D. ; Kovács, L. ; Docsa, T. ; Gergely, P. ; Somsák, L. / Crystallographic studies on α- and β-D-glucopyranosyl formamide analogues, inhibitors of glycogen phosphorylase. In: Biocatalysis and Biotransformation. 2003 ; Vol. 21, No. 4-5. pp. 233-242.
@article{f8af3112210c47778b0556019b546a55,
title = "Crystallographic studies on α- and β-D-glucopyranosyl formamide analogues, inhibitors of glycogen phosphorylase",
abstract = "The catalytic site of glycogen phosphorylase (GP) is currently under investigation as a target for inhibition of hepatic glycogenolysis under high glucose conditions. Three D-glucopyranosyl analogues, C-(1-azido-α-D-glucopyranosyl) formamide, C-(1-acetamido-α-D-glucopyranosyl) formamide, and C-(1-hydroxy-β-D-glucopyranosyl) formamide, were recognised as moderate competitive inhibitors of muscle glycogen phosphorylase b (GPb) [with respect to α-D-glucose 1-phosphate (Glc-l-P)] with Ki values of 1.80 (±0.2) mM, 0.31 (±0.01) mM, and 0.88 (±0.04) mM, respectively. In order to elucidate the structural basis of inhibition, we determined the structure of muscle GPb complexed with the three compounds at 2.1, 2.06 and 2.0 {\AA} resolution, respectively. The complex structures revealed that the inhibitors can be accommodated in the catalytic site of T-state GPb with very little change of the tertiary structure, and provide a rationalisation for understanding potency of the inhibitors. The glucopyranose moiety makes the standard hydrogen bonds and van der Waals contacts as observed in the GPb-glucose complex, while the substituent groups in the α- and β-position of the C1 atom make additional hydrogen bonding and van der Waals interactions to the protein.",
keywords = "Glucopyranosyl formamides, Glycogen phosphorylates, Inhibitor, Type 2 diabetes, X-ray crystallography",
author = "Chrysina, {E. D.} and Oikonomakos, {N. G.} and Zographos, {S. E.} and Kosmopoulou, {M. N.} and N. Bischler and Leonidas, {D. D.} and L. Kov{\'a}cs and T. Docsa and P. Gergely and L. Soms{\'a}k",
year = "2003",
month = "8",
doi = "10.1080/10242420310001614360",
language = "English",
volume = "21",
pages = "233--242",
journal = "Biocatalysis and Biotransformation",
issn = "1024-2422",
publisher = "Informa Healthcare",
number = "4-5",

}

TY - JOUR

T1 - Crystallographic studies on α- and β-D-glucopyranosyl formamide analogues, inhibitors of glycogen phosphorylase

AU - Chrysina, E. D.

AU - Oikonomakos, N. G.

AU - Zographos, S. E.

AU - Kosmopoulou, M. N.

AU - Bischler, N.

AU - Leonidas, D. D.

AU - Kovács, L.

AU - Docsa, T.

AU - Gergely, P.

AU - Somsák, L.

PY - 2003/8

Y1 - 2003/8

N2 - The catalytic site of glycogen phosphorylase (GP) is currently under investigation as a target for inhibition of hepatic glycogenolysis under high glucose conditions. Three D-glucopyranosyl analogues, C-(1-azido-α-D-glucopyranosyl) formamide, C-(1-acetamido-α-D-glucopyranosyl) formamide, and C-(1-hydroxy-β-D-glucopyranosyl) formamide, were recognised as moderate competitive inhibitors of muscle glycogen phosphorylase b (GPb) [with respect to α-D-glucose 1-phosphate (Glc-l-P)] with Ki values of 1.80 (±0.2) mM, 0.31 (±0.01) mM, and 0.88 (±0.04) mM, respectively. In order to elucidate the structural basis of inhibition, we determined the structure of muscle GPb complexed with the three compounds at 2.1, 2.06 and 2.0 Å resolution, respectively. The complex structures revealed that the inhibitors can be accommodated in the catalytic site of T-state GPb with very little change of the tertiary structure, and provide a rationalisation for understanding potency of the inhibitors. The glucopyranose moiety makes the standard hydrogen bonds and van der Waals contacts as observed in the GPb-glucose complex, while the substituent groups in the α- and β-position of the C1 atom make additional hydrogen bonding and van der Waals interactions to the protein.

AB - The catalytic site of glycogen phosphorylase (GP) is currently under investigation as a target for inhibition of hepatic glycogenolysis under high glucose conditions. Three D-glucopyranosyl analogues, C-(1-azido-α-D-glucopyranosyl) formamide, C-(1-acetamido-α-D-glucopyranosyl) formamide, and C-(1-hydroxy-β-D-glucopyranosyl) formamide, were recognised as moderate competitive inhibitors of muscle glycogen phosphorylase b (GPb) [with respect to α-D-glucose 1-phosphate (Glc-l-P)] with Ki values of 1.80 (±0.2) mM, 0.31 (±0.01) mM, and 0.88 (±0.04) mM, respectively. In order to elucidate the structural basis of inhibition, we determined the structure of muscle GPb complexed with the three compounds at 2.1, 2.06 and 2.0 Å resolution, respectively. The complex structures revealed that the inhibitors can be accommodated in the catalytic site of T-state GPb with very little change of the tertiary structure, and provide a rationalisation for understanding potency of the inhibitors. The glucopyranose moiety makes the standard hydrogen bonds and van der Waals contacts as observed in the GPb-glucose complex, while the substituent groups in the α- and β-position of the C1 atom make additional hydrogen bonding and van der Waals interactions to the protein.

KW - Glucopyranosyl formamides

KW - Glycogen phosphorylates

KW - Inhibitor

KW - Type 2 diabetes

KW - X-ray crystallography

UR - http://www.scopus.com/inward/record.url?scp=0347337763&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0347337763&partnerID=8YFLogxK

U2 - 10.1080/10242420310001614360

DO - 10.1080/10242420310001614360

M3 - Article

AN - SCOPUS:0347337763

VL - 21

SP - 233

EP - 242

JO - Biocatalysis and Biotransformation

JF - Biocatalysis and Biotransformation

SN - 1024-2422

IS - 4-5

ER -