NMR solution structure of lipocalin-type prostaglandin D synthase: evidence for partial overlapping of catalytic pocket and retinoic acid-binding pocket within the central cavity.

NMR solution structure of lipocalin-type prostaglandin D synthase: evidence for partial overlapping of catalytic pocket and retinoic acid-binding pocket within the central cavity. Research Abstract Details 

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NMR solution structure of lipocalin-type prostaglandin D synthase: evidence for partial overlapping of catalytic pocket and retinoic acid-binding pocket within the central cavity. Abstract Text:

Shigeru Shimamoto,Takuya Yoshida,Takashi Inui,Keigo Gohda,Yuji Kobayashi,Ko Fujimori,Toshiharu Tsurumura,Kosuke Aritake,Yoshihiro Urade,Tadayasu Ohkubo,Shigeru Shimamoto,Takuya Yoshida,Takashi Inui,Keigo Gohda,Yuji Kobayashi,Ko Fujimori,Toshiharu Tsurumura,Kosuke Aritake,Yoshihiro Urade,Tadayasu Ohkubo,

Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) catalyzes the isomerization of PGH(2), a common precursor of various prostanoids, to produce PGD(2), an endogenous somnogen and nociceptive modulator, in the brain. L-PGDS is a member of the lipocalin superfamily and binds lipophilic substances, such as retinoids and bile pigments, suggesting that L-PGDS is a dual functional protein acting as a PGD(2)-synthesizing enzyme and a transporter for lipophilic ligands. In this study we determined by NMR the three-dimensional structure of recombinant mouse L-PGDS with the catalytic residue Cys-65. The structure of L-PGDS exhibited the typical lipocalin fold, consisting of an eight-stranded, antiparallel beta-barrel and a long alpha-helix associated with the outer surface of the barrel. 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. Molecular docking studies, based on the result of NMR titration experiments with retinoic acid and PGH(2) analog, revealed that PGH(2) almost fully occupied the hydrophilic pocket 1, in which Cys-65 was located and all-trans-retinoic acid occupied the hydrophobic pocket 2, in which amino acid residues important for retinoid binding in other lipocalins were well conserved. Mutational and kinetic studies provide the direct evidence for the PGH(2) binding mode. These results indicated that the two binding sites for PGH(2) and retinoic acid in the large cavity of L-PGDS were responsible for the broad ligand specificity of L-PGDS and the non-competitive inhibition of L-PGDS activity by retinoic acid.

NMR solution structure of lipocalin-type prostaglandin D synthase: evidence for partial overlapping of catalytic pocket and retinoic acid-binding pocket within the central cavity. Publishing Authors By Initials

S Shimamoto,T Yoshida,T Inui,K Gohda,Y Kobayashi,K Fujimori,T Tsurumura,K Aritake,Y Urade,T Ohkubo,S Shimamoto,T Yoshida,T Inui,K Gohda,Y Kobayashi,K Fujimori,T Tsurumura,K Aritake,Y Urade,T Ohkubo,

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NMR solution structure of lipocalin-type prostaglandin D synthase: evidence for partial overlapping of catalytic pocket and retinoic acid-binding pocket within the central cavity. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: The Journal of biological chemistry

VOLUME: 282

Page Numbers: 31373-9

Journal Abbreviation: J. Biol. Chem.

ISSN: 0021-9258

DAY: 22

MONTH: 08

YEAR: 2007

NMR solution structure of lipocalin-type prostaglandin D synthase: evidence for partial overlapping of catalytic pocket and retinoic acid-binding pocket within the central cavity. Information

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LANGUAGE: eng

NlmUniqueID: 2985121

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Grant and Affiliation Information for NMR solution structure of lipocalin-type prostaglandin D synthase: evidence for partial overlapping of catalytic pocket and retinoic acid-binding pocket within the central cavity.

AFFILIATION: Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.

Country: United States

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MEDLINETA: J Biol Chem

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