spacer
spacer

PDBsum entry 2amv

Go to PDB code: 
protein ligands links
Transferase PDB id
2amv
Jmol
Contents
Protein chain
829 a.a. *
Ligands
PLP
BIN
GOL
Waters ×559
* Residue conservation analysis
PDB id:
2amv
Name: Transferase
Title: The structure of glycogen phosphorylase b with an alkyl- dihydropyridine-dicarboxylic acid
Structure: Protein (glycogen phosphorylase). Chain: a. Ec: 2.4.1.1
Source: Oryctolagus cuniculus. Rabbit. Organism_taxid: 9986. Tissue: muscle
Biol. unit: Dimer (from PDB file)
Resolution:
2.30Å     R-factor:   0.201     R-free:   0.282
Authors: S.E.Zographos,N.G.Oikonomakos,L.N.Johnson
Key ref:
S.E.Zographos et al. (1997). The structure of glycogen phosphorylase b with an alkyldihydropyridine-dicarboxylic acid compound, a novel and potent inhibitor. Structure, 5, 1413-1425. PubMed id: 9384557 DOI: 10.1016/S0969-2126(97)00292-X
Date:
13-Oct-98     Release date:   21-Oct-98    
Supersedes: 1amv
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00489  (PYGM_RABIT) -  Glycogen phosphorylase, muscle form
Seq:
Struc:
 
Seq:
Struc:
843 a.a.
829 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.4.1.1  - Glycogen phosphorylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      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 
  GO annot!
  Biological process     metabolic process   4 terms 
  Biochemical function     catalytic activity     7 terms  

 

 
    Added reference    
 
 
DOI no: 10.1016/S0969-2126(97)00292-X Structure 5:1413-1425 (1997)
PubMed id: 9384557  
 
 
The structure of glycogen phosphorylase b with an alkyldihydropyridine-dicarboxylic acid compound, a novel and potent inhibitor.
S.E.Zographos, N.G.Oikonomakos, K.E.Tsitsanou, D.D.Leonidas, E.D.Chrysina, V.T.Skamnaki, H.Bischoff, S.Goldmann, K.A.Watson, L.N.Johnson.
 
  ABSTRACT  
 
BACKGROUND: In muscle and liver, glycogen concentrations are regulated by the reciprocal activities of glycogen phosphorylase (GP) and glycogen synthase. An alkyl-dihydropyridine-dicarboxylic acid has been found to be a potent inhibitor of GP, and as such has potential to contribute to the regulation of glycogen metabolism in the non-insulin-dependent diabetes diseased state. The inhibitor has no structural similarity to the natural regulators of GP. We have carried out structural studies in order to elucidate the mechanism of inhibition. RESULTS: Kinetic studies with rabbit muscle glycogen phosphorylase b (GPb) show that the compound (-)(S)-3-isopropyl 4-(2-chlorophenyl)-1,4-dihydro-1-ethyl-2-methyl-pyridine-3,5, 6-tricarboxylate (Bay W1807) has a Ki = 1.6 nM and is a competitive inhibitor with respect to AMP. The structure of the cocrystallised GPb-W1807 complex has been determined at 100K to 2.3 A resolution and refined to an R factor of 0.198 (Rfree = 0.287). W1807 binds at the GPb allosteric effector site, the site which binds AMP, glucose-6-phosphate and a number of other phosphorylated ligands, and induces conformational changes that are characteristic of those observed with the naturally occurring allosteric inhibitor, glucose-6-phosphate. The dihydropyridine-5,6-dicarboxylate groups mimic the phosphate group of ligands that bind to the allosteric site and contact three arginine residues. CONCLUSIONS: The high affinity of W1807 for GP appears to arise from the numerous nonpolar interactions made between the ligand and the protein. Its potency as an inhibitor results from the induced conformational changes that lock the enzyme in a conformation known as the T' state. Allosteric enzymes, such as GP, offer a new strategy for structure-based drug design in which the allosteric site can be exploited. The results reported here may have important implications in the design of new therapeutic compounds.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. The chemical structures of (a) 1-alkyl-1,4 dihydropyridine-2,3-dicarboxylic acid and (b) Bay W1807.
 
  The above figure is reprinted by permission from Cell Press: Structure (1997, 5, 1413-1425) copyright 1997.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
17600143 C.Tiraidis, K.M.Alexacou, S.E.Zographos, D.D.Leonidas, T.Gimisis, and N.G.Oikonomakos (2007).
FR258900, a potential anti-hyperglycemic drug, binds at the allosteric site of glycogen phosphorylase.
  Protein Sci, 16, 1773-1782.
PDB code: 2off
16523484 C.M.Lukacs, N.G.Oikonomakos, R.L.Crowther, L.N.Hong, R.U.Kammlott, W.Levin, S.Li, C.M.Liu, D.Lucas-McGady, S.Pietranico, and L.Reik (2006).
The crystal structure of human muscle glycogen phosphorylase a with bound glucose and AMP: an intermediate conformation with T-state and R-state features.
  Proteins, 63, 1123-1126.
PDB code: 1z8d
16245298 G.Archontis, K.A.Watson, Q.Xie, G.Andreou, E.D.Chrysina, S.E.Zographos, N.G.Oikonomakos, and M.Karplus (2005).
Glycogen phosphorylase inhibitors: a free energy perturbation analysis of glucopyranose spirohydantoin analogues.
  Proteins, 61, 984-998.  
15987904 N.G.Oikonomakos, M.N.Kosmopoulou, E.D.Chrysina, D.D.Leonidas, I.D.Kostas, K.U.Wendt, T.Klabunde, and E.Defossa (2005).
Crystallographic studies on acyl ureas, a new class of glycogen phosphorylase inhibitors, as potential antidiabetic drugs.
  Protein Sci, 14, 1760-1771.
PDB codes: 1wut 1wuy 1wv0 1wv1
12838268 S.J.Teague (2003).
Implications of protein flexibility for drug discovery.
  Nat Rev Drug Discov, 2, 527-541.  
12203222 S.H.Hansen, and J.G.McCormack (2002).
Application of (13)C-filtered (1)H NMR to evaluate drug action on gluconeogenesis and glycogenolysis simultaneously in isolated rat hepatocytes.
  NMR Biomed, 15, 313-319.  
11358692 A.C.Anderson, R.H.O'Neil, T.S.Surti, and R.M.Stroud (2001).
Approaches to solving the rigid receptor problem by identifying a minimal set of flexible residues during ligand docking.
  Chem Biol, 8, 445-457.
PDB code: 1f28
11340058 J.L.Buchbinder, V.L.Rath, and R.J.Fletterick (2001).
Structural relationships among regulated and unregulated phosphorylases.
  Annu Rev Biophys Biomol Struct, 30, 191-209.  
11227044 J.L.Treadway, P.Mendys, and D.J.Hoover (2001).
Glycogen phosphorylase inhibitors for treatment of type 2 diabetes mellitus.
  Expert Opin Investig Drugs, 10, 439-454.  
10873856 N.G.Oikonomakos, V.T.Skamnaki, K.E.Tsitsanou, N.G.Gavalas, and L.N.Johnson (2000).
A new allosteric site in glycogen phosphorylase b as a target for drug interactions.
  Structure, 8, 575-584.
PDB code: 1c50
10980448 V.L.Rath, M.Ammirati, D.E.Danley, J.L.Ekstrom, E.M.Gibbs, T.R.Hynes, A.M.Mathiowetz, R.K.McPherson, T.V.Olson, J.L.Treadway, and D.J.Hoover (2000).
Human liver glycogen phosphorylase inhibitors bind at a new allosteric site.
  Chem Biol, 7, 677-682.
PDB codes: 1em6 1exv
  10211820 K.E.Tsitsanou, N.G.Oikonomakos, S.E.Zographos, V.T.Skamnaki, M.Gregoriou, K.A.Watson, L.N.Johnson, and G.W.Fleet (1999).
Effects of commonly used cryoprotectants on glycogen phosphorylase activity and structure.
  Protein Sci, 8, 741-749.
PDB codes: 1b4d 1bx3
  10548038 N.G.Oikonomakos, K.E.Tsitsanou, S.E.Zographos, V.T.Skamnaki, S.Goldmann, and H.Bischoff (1999).
Allosteric inhibition of glycogen phosphorylase a by the potential antidiabetic drug 3-isopropyl 4-(2-chlorophenyl)-1,4-dihydro-1-ethyl-2-methyl-pyridine-3,5,6-tricarbo xylate.
  Protein Sci, 8, 1930-1945.
PDB codes: 2gpa 3amv
  9568898 M.Gregoriou, M.E.Noble, K.A.Watson, E.F.Garman, T.M.Krulle, C.de la Fuente, G.W.Fleet, N.G.Oikonomakos, and L.N.Johnson (1998).
The structure of a glycogen phosphorylase glucopyranose spirohydantoin complex at 1.8 A resolution and 100 K: the role of the water structure and its contribution to binding.
  Protein Sci, 7, 915-927.
PDB codes: 1a8i 2gpn
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.