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; Yoshihiro Urade

doi:10.1093/jb/mvh033

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

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Tsuyoshi Inoue
Department of Materials Chemistry, Graduate School of Engineering, Osaka University
Structure and Function of Biomolecules Group, PRESTO, Japan Science and Technology Agency
Yousuke Okano
Department of Materials Chemistry, Graduate School of Engineering, Osaka University
Yuji Kado
Department of Materials Chemistry, Graduate School of Engineering, Osaka University
Kousuke Aritake
Department of Molecular Behavioral Biology, Japan Science and Technology Corporation, Osaka Bioscience Institute
Daisuke Irikura
Department of Molecular Behavioral Biology, Japan Science and Technology Corporation, Osaka Bioscience Institute
Nobuko Uodome
Department of Molecular Behavioral Biology, Japan Science and Technology Corporation, Osaka Bioscience Institute
Nobuo Okazaki
Department of Materials Chemistry, Graduate School of Engineering, Osaka University
Shigehiro Kinugasa
Department of Materials Chemistry, Graduate School of Engineering, Osaka University
Hideyuki Shishitani
Department of Materials Chemistry, Graduate School of Engineering, Osaka University
Hiroyoshi Matsumura
Department of Materials Chemistry, Graduate School of Engineering, Osaka University
Yasushi Kai
Department of Materials Chemistry, Graduate School of Engineering, Osaka University
Yoshihiro Urade
Department of Molecular Behavioral Biology, Japan Science and Technology Corporation, Osaka Bioscience Institute

Keywords: anti-allergic drug, hematopoietic prostaglandin D synthase, inhibitor complex, structure-based drug design, X-ray structure

JOURNAL FREE ACCESS

2004 Volume 135 Issue 3 Pages 279-283

DOI https://doi.org/10.1093/jb/mvh033

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Abstract

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 Trp 104, inducing large movement around the α 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 K_m 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.

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