PDBsum entry 2off

Transferase

PDB id: 2off

Contents

Protein chain

810 a.a. *

Ligands

OFF

Waters ×290

* Residue conservation analysis

PDB id:

2off

Name:

Transferase

Title:

The crystal structure of glycogen phosphorylase b in complex with a potent allosteric inhibitor

Structure:

Glycogen phosphorylase, muscle form. Chain: a. Synonym: myophosphorylase. Ec: 2.4.1.1

Source:

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

Resolution:

2.20Å R-factor: 0.185 R-free: 0.213

Authors:

C.Tiraidis,K.-M.Alexacou,S.E.Zographos,D.D.Leonidas,T.Gimisis, N.G.Oikonomakos

Key ref:

C.Tiraidis et al. (2007). FR258900, a potential anti-hyperglycemic drug, binds at the allosteric site of glycogen phosphorylase. Protein Sci, 16, 1773-1782. PubMed id: 17600143 DOI: 10.1110/ps.072925607

Date:

03-Jan-07 Release date: 07-Aug-07

Protein chain

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

Seq: 843 a.a.

Struc: 810 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

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

Added reference

DOI no: 10.1110/ps.072925607

Protein Sci 16:1773-1782 (2007)

PubMed id: 17600143

FR258900, a potential anti-hyperglycemic drug, binds at the allosteric site of glycogen phosphorylase.

C.Tiraidis, K.M.Alexacou, S.E.Zographos, D.D.Leonidas, T.Gimisis, N.G.Oikonomakos.

ABSTRACT

FR258900 has been discovered as a novel inhibitor of human liver glycogen phosphorylase a and proved to suppress hepatic glycogen breakdown and reduce plasma glucose concentrations in diabetic mice models. To elucidate the mechanism of inhibition, we have determined the crystal structure of the cocrystallized rabbit muscle glycogen phosphorylase b-FR258900 complex and refined it to 2.2 A resolution. The structure demonstrates that the inhibitor binds at the allosteric activator site, where the physiological activator AMP binds. The contacts from FR258900 to glycogen phosphorylase are dominated by nonpolar van der Waals interactions with Gln71, Gln72, Phe196, and Val45' (from the symmetry-related subunit), and also by ionic interactions from the carboxylate groups to the three arginine residues (Arg242, Arg309, and Arg310) that form the allosteric phosphate-recognition subsite. The binding of FR258900 to the protein promotes conformational changes that stabilize an inactive T-state quaternary conformation of the enzyme. The ligand-binding mode is different from those of the potent phenoxy-phthalate and acyl urea inhibitors, previously described, illustrating the broad specificity of the allosteric site.

Selected figure(s)

Figure 3.
Figure 3. A schematic diagram of the T-state rmGPb dimeric molecule,

Figure 7.
Figure 7. Comparison of the position of the inhibitor FR258900 as

The above figures are reprinted by permission from the Protein Society: Protein Sci (2007, 16, 1773-1782) copyright 2007.

Figures were selected by the author.

Author's comment

Isolated from the cultured broth of a fungal strain No. 13835 compound FR258900) proved effective in lowering plasma glucose levels in animal models of diabetes. The X-ray crystallographic study of RMGPb in complex with FR258900 showed that the compound binds at the allosteric site, at the subunit-subunit interface of the dimer with a high affinity (Ki = 0.46 mikroM).
N.G. Oikonomakos