title: Human hematopoietic prostaglandin D synthase inhibitor complex structures.
abstract: In mast and Th2 cells, hematopoietic prostaglandin (PG) D synthase (H-PGDS) catalyses the isomerization of PGH(2) in the presence of glutathione (GSH) to produce the allergic and inflammatory mediator PGD(2). We determined the X-ray structures of human H-PGDS inhibitor complexes with 1-amino-4-{4-[4-chloro-6-(2-sulpho-phenylamino)-[1,3,5]triazin-2-ylmethyl]-3-sulpho-phenylamino}-9,10-dioxo-9,10-dihydro-anthracene-2-sulphonic acid (Cibacron Blue) and 1-amino-4-(4-aminosulphonyl) phenyl-anthraquinone-2-sulphonic acid (APAS) at 2.0 Å resolution. When complexed with H-PGDS, Cibacron Blue had an IC(50) value of 40 nM and APAS 2.1 μM. The Cibacron Blue molecule was stabilized by four hydrogen bonds and π-π stacking between the anthraquinone ring and Trp104, the ceiling of the active site H-PGDS pocket. Among the four hydrogen bonds, the Cibacron Blue terminal sulphonic group directly interacted with conserved residues Lys112 and Lys198, which recognize the PGH(2) substrate α-chain. In contrast, the APAS anthraquinone ring was inverted to interact with Trp104, while its benzenesulphonic group penetrated the GSH-bound region at the bottom of the active site. Due to the lack of extended aromatic rings, APAS could not directly hydrogen bond with the two conserved lysine residues, thus decreasing the total number of hydrogen bond from four to one. These factors may contribute to the 50-fold difference in the IC(50) values obtained for the two inhibitors.
authors.affiliation: Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamada-Oka, Suita, Osaka 565-0871, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kado
authors.forename: Kosuke
authors.initials: K
authors.lastname: Aritake
authors.forename: Nobuko
authors.initials: N
authors.lastname: Uodome
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Okano
authors.forename: Nobuo
authors.initials: N
authors.lastname: Okazaki
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Matsumura
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Urade
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Inoue
mesh_terms: D000880:Anthraquinones / Q000737:chemistry*; D002118:Calcium / Q000737:chemistry; D020134:Catalytic Domain; D003067:Coenzymes / Q000737:chemistry; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005978:Glutathione / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D007700:Kinetics; D054834:Lipocalins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D014227:Triazines / Q000737:chemistry*
chemical_list: D000880:Anthraquinones; D003067:Coenzymes; D004791:Enzyme Inhibitors; D054834:Lipocalins; D014227:Triazines; C012842:Cibacron Blue F 3GA; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D005978:Glutathione; D002118:Calcium