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J. Biochem, 2004, Vol. 135, No. 3 279-283
© 2004 The Japanese Biochemical Society

BIOCHEMISTRY

First Determination of the Inhibitor Complex Structure of Human Hematopoietic Prostaglandin D Synthase

Tsuyoshi Inoue1,2, Yousuke Okano1, Yuji Kado1, Kousuke Aritake3, Daisuke Irikura3, Nobuko Uodome3, Nobuo Okazaki1, Shigehiro Kinugasa1, Hideyuki Shishitani1, Hiroyoshi Matsumura1, Yasushi Kai*,1 and Yoshihiro Urade*,3

1 Department of Materials Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871; 2 Structure and Function of Biomolecules Group, PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama; and 3 Department of Molecular Behavioral Biology, Japan Science and Technology Corporation, Osaka Bioscience Institute, Osaka 565-0874

Hematopoietic prostaglandin (PG) D synthase (H-PGDS) is responsible for the production of PGD2 as an allergy or inflammation mediator in mast and Th2 cells. We determined the X-ray structure of human H-PGDS complexed with an inhibitor, 2-(2'-benzothiazolyl)-5-styryl-3-(4'-phthalhydrazidyl) tetrazolium chloride (BSPT) at 1.9 Å resolution in the presence of Mg2+. The styryl group of the inhibitor penetrated to the bottom of the active site cleft, and the tetrazole ring was stabilized by the stacking interaction with Trp104, inducing large movement around the {alpha}5-helix, which caused the space group of the complex crystal to change from P21 to P1 upon binding of BSPT. The phthalhydrazidyl group of BSPT exhibited steric hindrance due to the cofactor, glutathione (GSH), increasing the IC50 value of BSPT for human H-PGDS from 36.2 µM to 98.1 µM upon binding of Mg2+, because the Km value of GSH for human H-PGDS was decreased from 0.60 µM in the presence of EDTA to 0.14 µM in the presence of Mg2+. We have to avoid steric hindrance of the GSH molecule that was stabilized by intracellular Mg2+ in the mM range in the cytosol for further development of structure-based anti-allergic drugs.

* To whom correspondence should be addressed. Dr. Yoshihiro Urade, Tel: +81-6-6872-4851, Fax: +81-6-6872-2841, E-mail: uradey{at}obi.or.jp; or Dr. Yasushi Kai, Tel: +81-6-6879-7410, Fax: +81-6-6879-7409, E-mail: kai{at}chem.eng.osaka-u.ac.jp


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K. Aritake, Y. Kado, T. Inoue, M. Miyano, and Y. Urade
Structural and Functional Characterization of HQL-79, an Orally Selective Inhibitor of Human Hematopoietic Prostaglandin D Synthase
J. Biol. Chem., June 2, 2006; 281(22): 15277 - 15286.
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