2CVD

Crystal structure analysis of human hematopoietic prostaglandin D synthase complexed with HQL-79

Summary for 2CVD

• Entry DOI: 10.2210/pdb2cvd/pdb
• Related: 1IYH 1IYI
• Descriptor: Glutathione-requiring prostaglandin D synthase, MAGNESIUM ION, GLUTATHIONE, ... (6 entities in total)
• Functional Keywords: glutathione-s-transferase, isomerase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: O60760
• Total number of polymer chains: 4
• Total formula weight: 96459.41

Authors

Aritake, K.,Kado, Y.,Inoue, T.,Miyano, M.,Urade, Y. (deposition date: 2005-06-02, release date: 2006-04-18, Last modification date: 2023-10-25)

Primary citation

Aritake, K.,Kado, Y.,Inoue, T.,Miyano, M.,Urade, Y.
Structural and Functional Characterization of HQL-79, an Orally Selective Inhibitor of Human Hematopoietic Prostaglandin D Synthase.
J.Biol.Chem., 281:15277-15286, 2006

PubMed Abstract: We determined the crystal structure of human hematopoietic prostaglandin (PG) D synthase (H-PGDS) as the quaternary complex with glutathione (GSH), Mg2+, and an inhibitor, HQL-79, having anti-inflammatory activities in vivo, at a 1.45-A resolution. In the quaternary complex, HQL-79 was found to reside within the catalytic cleft between Trp104 and GSH. HQL-79 was stabilized by interaction of a phenyl ring of its diphenyl group with Trp104 and by its piperidine group with GSH and Arg14 through water molecules, which form a network with hydrogen bonding and salt bridges linked to Mg2+. HQL-79 inhibited human H-PGDS competitively against the substrate PGH2 and non-competitively against GSH with Ki of 5 and 3 microm, respectively. Surface plasmon resonance analysis revealed that HQL-79 bound to H-PGDS with an affinity that was 12-fold higher in the presence of GSH and Mg2+ (Kd, 0.8 microm) than in their absence. Mutational studies revealed that Arg14 was important for the Mg2+-mediated increase in the binding affinity of H-PGDS for HQL-79, and that Trp104, Lys112, and Lys198 were important for maintaining the HQL-binding pocket. HQL-79 selectively inhibited PGD2 production by H-PGDS-expressing human megakaryocytes and rat mastocytoma cells with an IC50 value of about 100 microm but only marginally affected the production of other prostanoids, suggesting the tight functional engagement between H-PGDS and cyclooxygenase. Orally administered HQL-79 (30 mg/kg body weight) inhibited antigen-induced production of PGD2, without affecting the production of PGE2 and PGF2alpha, and ameliorated airway inflammation in wild-type and human H-PGDS-overexpressing mice. Knowledge about this structure of quaternary complex is useful for understanding the inhibitory mechanism of HQL-79 and should accelerate the structure-based development of novel anti-inflammatory drugs that inhibit PGD2 production specifically.

PubMed: 16547010
DOI: 10.1074/jbc.M506431200

Experimental method

X-RAY DIFFRACTION (1.45 Å)