Ligand Recognition Mechanism of Lipocalin-type Prostaglandin D Synthase

被引:2
作者
Shimamoto, Shigeru [1 ,2 ]
Yoshida, Takuya [2 ]
Ohkubo, Tadayasu [2 ]
机构
[1] Kinki Univ, Fac Sci & Technol, Osaka 5778502, Japan
[2] Osaka Univ, Grad Sch Pharmaceut Sci, Suita, Osaka 5650871, Japan
来源
YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN | 2011年 / 131卷 / 11期
关键词
lipocalin; prostaglandin D-2; prostaglandin H-2; NMR; BINDING-PROTEIN; ACID; NMR; OLIGODENDROCYTES; BILIVERDIN; BILIRUBIN; FAMILY; TRACE;
D O I
10.1248/yakushi.131.1575
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is a multi functional protein acting as a PGD(2), synthesizing enzyme, a transporter or scavenger of various lipophilic ligands, and an amyloid beta chaperon in the brain. L-PGDS is a member of the lipocalin superfamily and has the ability to bind various lipophilic molecules such as prostanoid, retinoid, bile pigment, and amyloid beta peptide. However, the molecular mechanism for a wide variety of ligand binding has not been well understood. In this study, we determined by NMR the structure of recombinant mouse L-PGDS and L-PGDS/PGH(2) analog complex. L-PGDS has the typical lipocalin fold, consisting of an eight-stranded beta-barrel and a long alpha-helix. The interior of the barrel formed a hydrophobic cavity opening to the upper end of the barrel, the size of which was larger than those of other lipocalins and the cavity contained two pockets. Kinetic studies and molecular docking studies based on the result of NMR titration experiments provide the direct evidence for two binding sites for PGH(2) and retinoic acid in the large cavity of L-PGDS. Structural comparison of L-PGDS/U-46619 complex with apo-L-PGDS showed that the H2-helix, CD-loop, and EF-loop located at the upper end of the beta-barrel change the conformation to cover the entry of the cavity upon U-46619 binding. These results indicated that the two binding sites in the large cavity and induced fit mechanism were responsible for the broad ligand specificity of L-PGDS.
引用
收藏
页码:1575 / 1581
页数:7
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