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

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) tetrazoli...

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Bibliographic Details
Published in:Journal of biochemistry (Tokyo) 2004-03, Vol.135 (3), p.279-283
Main Authors: Inoue, Tsuyoshi, Okano, Yousuke, Kado, Yuji, Aritake, Kousuke, Irikura, Daisuke, Uodome, Nobuko, Okazaki, Nobuo, Kinugasa, Shigehiro, Shishitani, Hideyuki, Matsumura, Hiroyoshi, Kai, Yasushi, Urade, Yoshihiro
Format: Article
Language:English
Subjects:
2-(2′-benzothiazolyl)-5-styryl-3-(4′-phthalhydrazidyl) tetrazolium chloride
anti-allergic drug
Benzothiazoles
BSPT
Crystallography, X-Ray
glutathione
glutathione S-transferase
GSH
GST
H-PGDS
hematopoietic prostaglandin D synthase
Hematopoietic System - enzymology
Humans
inhibitor complex
Intramolecular Oxidoreductases - antagonists & inhibitors
Intramolecular Oxidoreductases - chemistry
Lipocalins
Models, Molecular
PGD2
postaglandin D2
prostaglandin
structure-based drug design
Tetrazolium Salts - chemistry
Tetrazolium Salts - pharmacology
X-ray structure
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Summary: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.
ISSN:0021-924X
1756-2651
DOI:10.1093/jb/mvh033