2cvd
From Proteopedia
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'''Crystal structure analysis of human hematopoietic prostaglandin D synthase complexed with HQL-79''' | '''Crystal structure analysis of human hematopoietic prostaglandin D synthase complexed with HQL-79''' | ||
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[[Category: Miyano, M.]] | [[Category: Miyano, M.]] | ||
[[Category: Urade, Y.]] | [[Category: Urade, Y.]] | ||
| - | [[Category: | + | [[Category: Glutathione-s-transferase]] |
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| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 23:08:53 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 20:08, 3 May 2008
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. 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 Page seeded by OCA on Sat May 3 23:08:53 2008
