Human hematopoietic prostaglandin D synthase inhibitor complex structures
| Autor: | Nobuo Okazaki, Yuji Kado, Hiroyoshi Matsumura, Kosuke Aritake, Yousuke Okano, Yoshihiro Urade, Tsuyoshi Inoue, Nobuko Uodome |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Stereochemistry Lysine Coenzymes Prostaglandin Anthraquinones Crystallography X-Ray Biochemistry Anthraquinone Protein Structure Secondary chemistry.chemical_compound Protein structure Catalytic Domain Humans Molecule Enzyme Inhibitors Protein Structure Quaternary Molecular Biology biology Triazines Hydrogen bond Active site Hydrogen Bonding General Medicine Glutathione Lipocalins Intramolecular Oxidoreductases Kinetics chemistry biology.protein Calcium Protein Binding |
| Zdroj: | Journal of Biochemistry. 151:447-455 |
| ISSN: | 0021-924X |
| DOI: | 10.1093/jb/mvs024 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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