Journal Article

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

Tsuyoshi Inoue, Yousuke Okano, Yuji Kado, Kousuke Aritake, Daisuke Irikura, Nobuko Uodome, Nobuo Okazaki, Shigehiro Kinugasa, Hideyuki Shishitani, Hiroyoshi Matsumura, Yasushi Kai and Yoshihiro Urade

in The Journal of Biochemistry

Published on behalf of The Japanese Biochemical Society

Volume 135, issue 3, pages 279-283
Published in print March 2004 | ISSN: 0021-924X
Published online March 2004 | e-ISSN: 1756-2651 | DOI:
First Determination of the Inhibitor Complex Structure of Human Hematopoietic Prostaglandin D Synthase

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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 α5-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.

Keywords: anti-allergic drug, hematopoietic prostaglandin D synthase, inhibitor complex, structure-based drug design, X-ray structure.; PG, prostaglandin; H-PGDS, hematopoietic prostaglandin D synthase; BSPT, 2-(2′-benzothiazolyl)-5-styryl-3-(4′-phthalhydrazidyl) tetrazolium chloride; PGD2, postaglandin D2; GST, glutathione S-transferase; GSH, glutathione.

Journal Article.  2800 words.  Illustrated.

Subjects: Biochemistry

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