PDBsum entry: 1c50

Transferase

PDB id: 1c50

Contents

Protein chain

830 a.a. *

Ligands

PLP

CHI

Waters ×256

* Residue conservation analysis

PDB id:

1c50

Name:

Transferase

Title:

Identification and structural characterization of a novel al binding site of glycogen phosphorylase b

Structure:

Protein (glycogen phosphorylase). Chain: a. Ec: 2.4.1.1

Source:

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

Resolution:

2.30Å R-factor: 0.199 R-free: 0.246

Authors:

N.G.Oikonomakos,V.T.Skamnaki,K.E.Tsitsanou,N.G.Gavalas,L.N.J

Key ref:

N.G.Oikonomakos et al. (2000). A new allosteric site in glycogen phosphorylase b as a target for drug interactions. Structure, 8, 575-584. PubMed id: 10873856 DOI: 10.1016/S0969-2126(00)00144-1

Date:

15-Dec-99 Release date: 23-Dec-99

Protein chain

P00489  (PYGM_RABIT) -  Glycogen phosphorylase, muscle form

Seq: 843 a.a.

Struc: 830 a.a.*

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

Enzyme reactions

• Enzyme class: E.C.2.4.1.1 - 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

 Gene Ontology (GO) functional annotation 

• Cellular component: cytosol (1 term)
• Biological process: metabolic process (4 terms)
• Biochemical function: catalytic activity (7 terms)

reference

DOI no: 10.1016/S0969-2126(00)00144-1

Structure 8:575-584 (2000)

PubMed id: 10873856

A new allosteric site in glycogen phosphorylase b as a target for drug interactions.

N.G.Oikonomakos, V.T.Skamnaki, K.E.Tsitsanou, N.G.Gavalas, L.N.Johnson.

ABSTRACT

BACKGROUND: In muscle and liver, glycogen concentrations are regulated by the coordinated activities of glycogen phosphorylase (GP) and glycogen synthase. GP exists in two forms: the dephosphorylated low-activity form GPb and the phosphorylated high-activity form GPa. In both forms, allosteric effectors can promote equilibrium between a less active T state and a more active R state. GP is a possible target for drugs that aim to prevent unwanted glycogen breakdown and to stimulate glycogen synthesis in non-insulin-dependent diabetes. As a result of a data bank search, 5-chloro-1H-indole-2-carboxylic acid (1-(4-fluorobenzyl)-2-(4-hydroxypiperidin-1-yl)-2-oxoethy l)amide, CP320626, was identified as a potent inhibitor of human liver GP. Structural studies have been carried out in order to establish the mechanism of this unusual inhibitor. RESULTS: The structure of the cocrystallised GPb-CP320626 complex has been determined to 2.3 A resolution. CP320626 binds at a site located at the subunit interface in the region of the central cavity of the dimeric structure. The site has not previously been observed to bind ligands and is some 15 A from the AMP allosteric site and 33 A from the catalytic site. The contacts between GPb and CP320626 comprise six hydrogen bonds and extensive van der Waals interactions that create a tight binding site in the T-state conformation of GPb. In the R-state conformation of GPa these interactions are significantly diminished. CONCLUSIONS: CP320626 inhibits GPb by binding at a new allosteric site. Although over 30 A from the catalytic site, the inhibitor exerts its effects by stabilising the T state at the expense of the R state and thereby shifting the allosteric equilibrium between the two states. The new allosteric binding site offers a further recognition site in the search for improved GP inhibitors.

Selected figure(s)

Figure 1.
Fig. 1. The chemical structures of (a) CP91149 and (b) CP320626, showing the numbering system used.

The above figure is reprinted by permission from Cell Press: Structure (2000, 8, 575-584) copyright 2000.

Figure was selected by an automated process.