Comparison of PGH2 binding site in prostaglandin synthases

Abstract

Background: Prostaglandin H2 (PGH2) is a common precursor for the synthesis of five different Prostanoids via specific Prostanoid Synthases. The binding of this substrate with these Synthases is not properly understood. Moreover, currently no crystal structure of complexes bound with PGH2 has been reported. Hence, understanding the interactions of PGH2 and characterizing its binding sites in these synthases is crucial for developing novel therapeutics based on these proteins as targets.

Results: Shape and physico-chemical properties of the PGH2 binding sites of the four prostanoid synthases were analyzed and compared in order to understand the molecular basis of the specificity. This study provides models with predicted pockets for the binding of PGH2 with PGD, PGE, PGF and PGI Synthases. The results closely match with available experimental data. The comparison showed seven physico-chemical features that are common to the four PGH2 binding sites. However this common pattern is not statistically unique and is not specific enough to distinguish between proteins that can or cannot bind PGH2. A large scale search in ASTRAL data bank, a non redundant Protein Data Bank, for a similar pattern showed the uniqueness of each of the PGH2 binding site in these Synthases.

Conclusion: The binding pockets in PGDS, PGES, PGFS and PGIS are unique and do not share significant commonality which can be characterized as a PGH2 binding site. Local comparison of these protein structures highlights a case of convergent evolution in analogous functional sites.

Figure 1

Overlap of predicted PGH₂ binding site with the ligand binding site in the four synthases. The surface of the synthases are represented in cartoon and colored grey except the common active site residues represented in space-fill and are colored green. PGH₂ is colored red, and the other ligands in the crystal structure (IMN, HQL-79, 15 M and MDX) are colored blue. The figure is prepared using PyMol [36]

Figure 2

Superimposition of the four synthases based on transformations suggested by MultiBind. Spatial arrangement of the recognized features and the superimposition of the proteins and the PGH₂ ligands, according to the transformations suggested by MultiBind. The structures of the four proteins are represented by strands. PGDS - blue, PGES - red, PGFS - green and PGIS - gray. PGH₂ are represented as space fill and colored according to the protein. The ligand molecules are presented for verification purpose only and are not a part of the input to MultiBind. The figure is prepared using PyMol [36]

Figure 3

Family and reaction details of the seven prostaglandin synthases. *Reaction Schemes taken from the Kegg Database[37]