Human hematopoietic prostaglandin D synthase inhibitor complex structures.

Area of Science:

• Biochemistry
• Structural Biology
• Enzymology

Background:

• Hematopoietic prostaglandin D synthase (H-PGDS) is crucial for producing prostaglandin D2 (PGD2), a key mediator in allergic and inflammatory responses.
• PGD2 plays a significant role in mast cells and Th2 cells, making H-PGDS a potential therapeutic target.

Purpose of the Study:

• To elucidate the structural basis of inhibition for human H-PGDS.
• To understand the molecular interactions of two inhibitors, Cibacron Blue and APAS, with H-PGDS.
• To correlate structural findings with the observed inhibitory potencies (IC50 values).

Main Methods:

• X-ray crystallography was employed to determine the structures of human H-PGDS in complex with Cibacron Blue and APAS at 2.0 Å resolution.
• Enzyme inhibition assays were performed to determine the IC50 values for both inhibitors.

Main Results:

• The crystal structures revealed distinct binding modes for Cibacron Blue and APAS within the H-PGDS active site.
• Cibacron Blue exhibited a lower IC50 (40 nM) and formed four hydrogen bonds, including interactions with conserved residues Lys112 and Lys198.
• APAS had a higher IC50 (2.1 μM) due to fewer hydrogen bonds and a different binding orientation, interacting with Trp104 and the glutathione-binding region.

Conclusions:

• The structural differences in inhibitor binding explain the significant difference in inhibitory potency between Cibacron Blue and APAS.
• Understanding these interactions provides insights for designing more potent H-PGDS inhibitors for treating allergic and inflammatory diseases.