PDBsum entry 3ceh

Transferase

PDB id: 3ceh

Contents

Protein chain

794 a.a. *

Ligands

NBG ×2

PO4 ×2

PLP ×2

AVE ×2

MES

Waters ×508

* Residue conservation analysis

PDB id:

3ceh

Name:

Transferase

Title:

Human liver glycogen phosphorylase (tense state) in complex with the allosteric inhibitor ave5688

Structure:

Glycogen phosphorylase, liver form. Chain: a, b. Engineered: yes

Source:

Homo sapiens. Human. Gene: pygl. Expressed in: spodoptera frugiperda. Expression_system_cell_line: sf9.

Resolution:

2.80Å R-factor: 0.170 R-free: 0.247

Authors:

K.U.Wendt,M.K.Dreyer,O.Anderka,T.Klabunde,P.Loenze,E.Defossa, D.Schmoll

Key ref:

O.Anderka et al. (2008). Thermodynamic characterization of allosteric glycogen phosphorylase inhibitors. Biochemistry, 47, 4683-4691. PubMed id: 18373353

Date:

29-Feb-08 Release date: 27-May-08

Protein chains

P06737  (PYGL_HUMAN) -  Glycogen phosphorylase, liver form from Homo sapiens

Seq: 847 a.a.

Struc: 794 a.a.

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 = PLP) matches with 60.00% similarity)

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

Added reference

Biochemistry 47:4683-4691 (2008)

PubMed id: 18373353

Thermodynamic characterization of allosteric glycogen phosphorylase inhibitors.

O.Anderka, P.Loenze, T.Klabunde, M.K.Dreyer, E.Defossa, K.U.Wendt, D.Schmoll.

ABSTRACT

Glycogen phosphorylase (GP) is a validated target for the treatment of type 2 diabetes. Here we describe highly potent GP inhibitors, AVE5688, AVE2865, and AVE9423. The first two compounds are optimized members of the acyl urea series. The latter represents a novel quinolone class of GP inhibitors, which is introduced in this study. In the enzyme assay, both inhibitor types compete with the physiological activator AMP and act synergistically with glucose. Isothermal titration calorimetry (ITC) shows that the compounds strongly bind to nonphosphorylated, inactive GP (GPb). Binding to phosphorylated, active GP (GPa) is substantially weaker, and the thermodynamic profile reflects a coupled transition to the inactive (tense) conformation. Crystal structures confirm that the three inhibitors bind to the AMP site of tense state GP. These data provide the first direct evidence that acyl urea and quinolone compounds are allosteric inhibitors that selectively bind to and stabilize the inactive conformation of the enzyme. Furthermore, ITC reveals markedly different thermodynamic contributions to inhibitor potency that can be related to the binding modes observed in the cocrystal structures. For AVE5688, which occupies only the lower part of the bifurcated AMP site, binding to GPb (Kd = 170 nM) is exclusively enthalpic (Delta H = -9.0 kcal/mol, TDelta S = 0.3 kcal/mol). The inhibitors AVE2865 (Kd = 9 nM, Delta H = -6.8 kcal/mol, TDelta S = 4.2 kcal/mol) and AVE9423 (Kd = 24 nM, Delta H = -5.9 kcal/mol, TDelta S = 4.6 kcal/mol) fully exploit the volume of the binding pocket. Their pronounced binding entropy can be attributed to the extensive displacement of solvent molecules as well as to ionic interactions with the phosphate recognition site.