2cvd

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spinqualitylabelsall models 2cvd, resolution 1.45Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

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

Overview

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.

About this Structure

2CVD is a Single protein structure of sequence from Homo sapiens with MG, GSH, HQL and GOL as ligands. Full crystallographic information is available from OCA.

Reference

Structural and functional characterization of HQL-79, an orally selective inhibitor of human hematopoietic prostaglandin D synthase., Aritake K, Kado Y, Inoue T, Miyano M, Urade Y, J Biol Chem. 2006 Jun 2;281(22):15277-86. Epub 2006 Mar 17. PMID:16547010

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