PDBsum entry 2g9v

Transferase

PDB id: 2g9v

Contents

Protein chain

807 a.a. *

Ligands

PO4 ×2

IFM

Waters ×224

* Residue conservation analysis

PDB id:

2g9v

Name:

Transferase

Title:

The crystal structure of glycogen phosphorylase in complex with (3r, 4r,5r)-5-hydroxymethylpiperidine-3,4-diol and phosphate

Structure:

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

Source:

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

Resolution:

2.15Å R-factor: 0.196 R-free: 0.235

Authors:

N.G.Oikonomakos,C.Tiraidis,D.D.Leonidas,S.E.Zographos

Key ref:

N.G.Oikonomakos et al. (2006). Iminosugars as potential inhibitors of glycogenolysis: structural insights into the molecular basis of glycogen phosphorylase inhibition. J Med Chem, 49, 5687-5701. PubMed id: 16970395 DOI: 10.1021/jm060496g

Date:

07-Mar-06 Release date: 16-Jan-07

Protein chain

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

Seq: 843 a.a.

Struc: 807 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 (Bound ligand (Het Group name = PO4) corresponds exactly) = [(1->4)-alpha-D-glucosyl](n-1) + alpha-D-glucose 1-phosphate (Bound ligand (Het Group name = IFM) matches with 44.44% similarity)

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

Added reference

DOI no: 10.1021/jm060496g

J Med Chem 49:5687-5701 (2006)

PubMed id: 16970395

Iminosugars as potential inhibitors of glycogenolysis: structural insights into the molecular basis of glycogen phosphorylase inhibition.

N.G.Oikonomakos, C.Tiraidis, D.D.Leonidas, S.E.Zographos, M.Kristiansen, C.U.Jessen, L.Nørskov-Lauritsen, L.Agius.

ABSTRACT

Iminosugars DAB (5), isofagomine (9), and several N-substituted derivatives have been identified as potent inhibitors of liver glycogen phosphorylase a (IC(50) = 0.4-1.2 microM) and of basal and glucagon-stimulated glycogenolysis (IC(50) = 1-3 microM). The X-ray structures of 5, 9, and its N-3-phenylpropyl analogue 8 in complex with rabbit muscle glycogen phosphorylase (GPb) shows that iminosugars bind tightly at the catalytic site in the presence of the substrate phosphate and induce conformational changes that characterize the R-state conformation of the enzyme. Charged nitrogen N1 is within hydrogen-bonding distance with the carbonyl oxygen of His377 (5) and in ionic contact with the substrate phosphate oxygen (8 and 9). Our findings suggest that the inhibitors function as oxocarbenium ion transition-state analogues. The conformational change to the R state provides an explanation for previous findings that 5, unlike inhibitors that favor the T state, promotes phosphorylation of GPb in hepatocytes with sequential inactivation of glycogen synthase.