リポカリン型プロスタグランジンD合成酵素のリガンド認識機構

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概要

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•   Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is a multi functional protein acting as a PGD2 synthesizing enzyme, a transporter or scavenger of various lipophilic ligands, and an amyloid β 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 β 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/PGH2 analog complex. L-PGDS has the typical lipocalin fold, consisting of an eight-stranded β-barrel and a long α-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 PGH2 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 β-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.

著者

• 島本 茂

  阪大院・薬

• 吉田 卓也

  大阪大学大学院薬学研究科

• 島本 茂

  近畿大学理工学部生命科学科

• 大久保 忠恭

  大阪大学大学院薬学研究科

関連論文

• 2P037 リポカリン型プロスタグランジンD合成酵素の溶液構造(蛋白質(構造・構造機能相関),ポスター発表,第45回日本生物物理学会年会)
• リボソーム再生因子(RRF)の構造と機能(構造生物学(2))
• 特集によせて(構造生物学(2))
• NMRによるタンパク質とリガンドの相互作用解析(タンパク質間相互作用の定量的解析手法の新展開)
• リポカリン型プロスタグランジンD合成酵素のリガンド認識機構
• 創薬におけるITCの利用

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