PDBsum entry: 1l5r

Transferase

PDB id: 1l5r

Contents

Protein chains

790 a.a. *

Ligands

NBG

PLP ×2

700

RBF

MRD

Waters ×547

* Residue conservation analysis

PDB id:

1l5r

Name:

Transferase

Title:

Human liver glycogen phosphorylase a complexed with riboflav acetyl-beta-d-glucopyranosylamine and cp-403,700

Structure:

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

Source:

Homo sapiens. Human. Organism_taxid: 9606. Organ: liver. Expressed in: escherichia coli. Expression_system_taxid: 562

Biol. unit:

Dimer (from PDB file)

Resolution:

2.10Å R-factor: 0.247 R-free: 0.283

Authors:

J.L.Ekstrom,T.A.Pauly,M.D.Carty,W.C.Soeller,J.Culp,D.E.Danle D.J.Hoover,J.L.Treadway,E.M.Gibbs,R.J.Fletterick,Y.S.N.Day, D.G.Myszka,V.L.Rath

Key ref:

J.L.Ekstrom et al. (2002). Structure-activity analysis of the purine binding site of human liver glycogen phosphorylase. Chem Biol, 9, 915-924. PubMed id: 12204691 DOI: 10.1016/S1074-5521(02)00186-2

Date:

07-Mar-02 Release date: 04-Dec-02

Protein chains

P06737  (PYGL_HUMAN) -  Glycogen phosphorylase, liver form

Seq: 847 a.a.

Struc: 790 a.a.

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) (Bound ligand (Het Group name = NBG) matches with 55.56% similarity) + 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: soluble fraction (3 terms)
• Biological process: metabolic process (7 terms)
• Biochemical function: catalytic activity (16 terms)

reference

DOI no: 10.1016/S1074-5521(02)00186-2

Chem Biol 9:915-924 (2002)

PubMed id: 12204691

Structure-activity analysis of the purine binding site of human liver glycogen phosphorylase.

J.L.Ekstrom, T.A.Pauly, M.D.Carty, W.C.Soeller, J.Culp, D.E.Danley, D.J.Hoover, J.L.Treadway, E.M.Gibbs, R.J.Fletterick, Y.S.Day, D.G.Myszka, V.L.Rath.

ABSTRACT

Human liver glycogen phosphorylase (HLGP) catalyzes the breakdown of glycogen to maintain serum glucose levels and is a therapeutic target for diabetes. HLGP is regulated by multiple interacting allosteric sites, each of which is a potential drug binding site. We used surface plasmon resonance (SPR) to screen for compounds that bind to the purine allosteric inhibitor site. We determined the affinities of a series of compounds and solved the crystal structures of three representative ligands with K(D) values from 17-550 microM. The crystal structures reveal that the affinities are partly determined by ligand-specific water-mediated hydrogen bonds and side chain movements. These effects could not be predicted; both crystallographic and SPR studies were required to understand the important features of binding and together provide a basis for the design of new allosteric inhibitors targeting this site.

Selected figure(s)

Figure 2.
Figure 2. Purine Site ScreenFor each of the 18 compounds tested, the RU values at equilibrium versus ligand concentration were fitted to a 1:1 interaction model. The resulting fitted curves are superimposed and listed in order on the right starting from the curve closest to the upper left (riboflavin) to the curve closest to the lower right (allantoin), with the labels color coded to match their respective binding isotherms. For clarity, only the curves for riboflavin, caffeine, and uric acid are labeled directly.

Figure 3.
Figure 3. Crystal Structure of HLGPa/Purine Site Ligands(A), Uric acid bound at the purine site; (B), caffeine bound at the purine site; (C), riboflavin bound at the purine site. The 2F[o]-F[c] difference electron density for each ligand is contoured at 1σ above the mean. The figures were prepared using Ribbons [31], and each panel is colored as follows: structural elements of the N-terminal domain, red; those of the C-terminal domain, blue; oxygen atoms, red; nitrogen atoms, blue; carbon atoms, green; and water molecules are shown as red spheres.

The above figures are reprinted by permission from Cell Press: Chem Biol (2002, 9, 915-924) copyright 2002.