PDBsum entry 1k08

Transferase

PDB id: 1k08

Contents

Protein chain

817 a.a. *

Ligands

BZD ×2

PLP

Waters ×249

* Residue conservation analysis

PDB id:

1k08

Name:

Transferase

Title:

Crystallographic binding study of 10 mm n-benzoyl-n'-beta-d- glucopyranosyl urea to glycogen phosphorylase b

Structure:

Glycogen phosphorylase. Chain: a. Synonym: myophosphorylase. Ec: 2.4.1.1

Source:

Oryctolagus cuniculus. Rabbit. Organism_taxid: 9986. Tissue: muscle

Biol. unit:

Dimer (from PDB file)

Resolution:

2.26Å R-factor: 0.180 R-free: 0.212

Authors:

N.G.Oikonomakos,M.Kosmopoulou,S.E.Zographos,D.D.Leonidas, E.D.Chrysina,L.Somsak,V.Nagy,J.P.Praly,T.Docsa,B.Toth,P.Gergely

Key ref:

N.G.Oikonomakos et al. (2002). Binding of N-acetyl-N '-beta-D-glucopyranosyl urea and N-benzoyl-N '-beta-D-glucopyranosyl urea to glycogen phosphorylase b: kinetic and crystallographic studies. Eur J Biochem, 269, 1684-1696. PubMed id: 11895439 DOI: 10.1046/j.1432-1327.2002.02813.x

Date:

18-Sep-01 Release date: 03-Oct-01

Protein chain

P00489  (PYGM_RABIT) -  Glycogen phosphorylase, muscle form from Oryctolagus cuniculus

Seq: 843 a.a.

Struc: 817 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.2.4.1.1 - glycogen phosphorylase.
• Pathway: Glycogen
• Reaction: [(1->4)-alpha-D-glucosyl](n) + phosphate = [(1->4)-alpha-D-glucosyl](n-1) + alpha-D-glucose 1-phosphate

[(1->4)-alpha-D-glucosyl](n) + phosphate = [(1->4)-alpha-D-glucosyl](n-1) + alpha-D-glucose 1-phosphate (Bound ligand (Het Group name = PLP) matches with 63.16% similarity)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1046/j.1432-1327.2002.02813.x

Eur J Biochem 269:1684-1696 (2002)

PubMed id: 11895439

Binding of N-acetyl-N '-beta-D-glucopyranosyl urea and N-benzoyl-N '-beta-D-glucopyranosyl urea to glycogen phosphorylase b: kinetic and crystallographic studies.

N.G.Oikonomakos, M.Kosmopoulou, S.E.Zographos, D.D.Leonidas, E.D.Chrysina, L.Somsák, V.Nagy, J.P.Praly, T.Docsa, B.Tóth, P.Gergely.

ABSTRACT

Two substituted ureas of beta-D-glucose, N-acetyl-N'-beta-D-glucopyranosyl urea (Acurea) and N-benzoyl-N'-beta-D-glucopyranosyl urea (Bzurea), have been identified as inhibitors of glycogen phosphorylase, a potential target for therapeutic intervention in type 2 diabetes. To elucidate the structural basis of inhibition, we determined the structure of muscle glycogen phosphorylase b (GPb) complexed with the two compounds at 2.0 A and 1.8 A resolution, respectively. The structure of the GPb-Acurea complex reveals that the inhibitor can be accommodated in the catalytic site of T-state GPb with very little change in the tertiary structure. The glucopyranose moiety makes the standard hydrogen bonds and van der Waals contacts as observed in the GPb-glucose complex, while the acetyl urea moiety is in a favourable electrostatic environment and makes additional polar contacts with the protein. The structure of the GPb-Bzurea complex shows that Bzurea binds tightly at the catalytic site and induces substantial conformational changes in the vicinity of the catalytic site. In particular, the loop of the polypeptide chain containing residues 282-287 shifts 1.3-3.7 A (Calpha atoms) to accommodate Bzurea. Bzurea can also occupy the new allosteric site, some 33 A from the catalytic site, which is currently the target for the design of antidiabetic drugs.

Selected figure(s)

Figure 4.
Fig. 4. Stereo diagrams showing (A ) a comparison of Acurea bound to GPb (orange) with native GPb (white) in the vicinity of the catalytic site, and (B ) a comparison of Bzurea (orange) bound to GPb with native GPb (white) in the vicinity of the catalytic site.

Figure 8.
Fig. 8. Stereo diagram showing a comparison of Bzurea bound to GPb with CP320626 bound to GPb in the vicinity of the new allosteric site. Green: GPb–Bzurea complex (subunit 1); cyan: GPb–Bzurea complex (subunit 2); white: GPb–glucose–CP320626 complex. All figures were produced using xobjects (M. E. M. Noble, Laboratory of Molecular Biophysics, University of Oxford, UK, unpublished results).

The above figures are reprinted by permission from the Federation of European Biochemical Societies: Eur J Biochem (2002, 269, 1684-1696) copyright 2002.

Figures were selected by the author.

Author's comment

Understanding the events that regulate glycogen metabolism may provide a basis for therapy of type 2 diabetes. Glycogen phosphporylase (GP) catalyses the first step in glycogen degradation to yield Glc-1-P. In the liver, Glc-1-P, is mostly converted by phosphoglucomutase and glucose-6-phosphatase to glucose which is released for the benefit of other tissues. In response to nervous or hormonal signals GPb is converted to GPa through the phosphorylase kinase catalyzed addition of a phosphoryl group to the hydroxyl group of a specific serine at the N-terminus. The reverse reaction of dephosphorylation that inactivates the enzyme is catalyzed by protein phosphatase 1 (PP1), an enzyme that is regulated in response to insulin. The conversion of GPa to GPb relieves the allosteric inhibition that GPa exerts on the glycogen-associated PP1, which converts glycogen synthase D to the I form, thus allowing the phosphatase to stimulate the synthesis of glycogen. Because of its central role in the regulation of glycogen metabolism, GP has been a target for compounds that might control hyperglycaemia in type 2 diabetes.
Nikos G. Oikonomakos