3VI5

Human hematopoietic prostaglandin D synthase inhibitor complex structures

Summary for 3VI5

• Entry DOI: 10.2210/pdb3vi5/pdb
• Related: 1IYH 1IYI 1V40 2CVD 3VI7
• Descriptor: Hematopoietic prostaglandin D synthase, GLUTATHIONE, CALCIUM ION, ... (6 entities in total)
• Functional Keywords: sigma class glutathione s transferase(gst), isomerase, glutathione s transferase, ca binding, gsh binding, prostaglandin h2 binding, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: O60760
• Total number of polymer chains: 4
• Total formula weight: 94760.77

Authors

Kado, Y.,Inoue, T. (deposition date: 2011-09-21, release date: 2012-04-18, Last modification date: 2024-03-20)

Primary citation

Kado, Y.,Aritake, K.,Uodome, N.,Okano, Y.,Okazaki, N.,Matsumura, H.,Urade, Y.,Inoue, T.
Human hematopoietic prostaglandin D synthase inhibitor complex structures
J.Biochem., 151:447-455, 2012

PubMed 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.

PubMed: 22418579
DOI: 10.1093/jb/mvs024

Experimental method

X-RAY DIFFRACTION (2 Å)